CN106459045A - Heterocyclic kinase inhibitors - Google Patents

Heterocyclic kinase inhibitors Download PDF

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CN106459045A
CN106459045A CN201580031633.1A CN201580031633A CN106459045A CN 106459045 A CN106459045 A CN 106459045A CN 201580031633 A CN201580031633 A CN 201580031633A CN 106459045 A CN106459045 A CN 106459045A
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base
triazole
amino
optionally substituted
pyrazine
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M.M.弗里曼
P.科克斯
K.E.弗兰克
M.Z.赫曼
A.奥苏马
N.S.威尔逊
X.徐
K.库萨克
R.亨特利
J.M.赫罗尔德
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AbbVie Inc
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Abstract

The present invention provides compounds of formula (I), pharmaceutically acceptable salts, prodrugs, biologically active metabolites, stereoisomers and isomers thereof, wherein the variables are defined herein. The compounds of the invention are useful for the treatment of immunological and cancer disorders.

Description

Heterocyclic kinase inhibitors
The quoting of related application
This application claims the applying date of international application the PCT/CN2014/075560th of on April 17th, 2014 submission Priority and rights and interests, entire contents are incorporated herein by reference.
The background of the present invention
These protein kinases represent big protein familieses, and these protein are in diversified cell processes Adjust and play central role in the maintenance with cell function.The nonrestrictive list of the part of these kinases includes：Non- receptor Tyrosine kinase, such as Tec family (BTK, ITK, Tec, ETK/BMX＆RLK/TXK), Janus kinase families (Jak1, Jak2, Jak3 and Tyk2)；Merge kinases, such as BCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk；Receptor tyrosine kinase, Such as colony-stimulating factor 1 receptor (CSF-1R), EGF-R ELISA (EGFR), platelet-derived growth factor receptorses Kinases (PDGF-R), the receptor kinase of stem cell factor, c-kit, C-MET HGFr, c-Met and fibroblast Growth factor receptorses, FGFR3；And serine/threonine kinase, such as b-RAF, mitogen activated protein kinases are (for example, ) and SAPK2 β MKK6.Observe abnormal kinase activity in numerous disease state, described morbid state includes benign and malignant increasing Natural disposition disorder and the disease being led to due to the improper activation of immune system and nervous system.The compounds suppression of the present invention The activity of one or more protein kinase, and therefore it is expected to useful in treating kinase mediated disease.
Bruton's (Bruton ' s) tyrosine kinase (BTK) are nonreceptor tyrosine kinases, and it is in many hematopoietic cells (include B cell, platelet, mastocyte, basophilic granulocyte, eosinophilic granulocyte, macrophage and neutrophilic granulocyte and Participate in osteoclasia osteoclast) in immunity receptor signal (BCR, Fc ε R, Fc γ R, DAP12, Dectin-1, GPVI etc.) in There is pivotal role (referring to Bruner (Brunner) et al., 2005 histologys and histopathology (Histol.Histopathol.), 20:945, Mo Hanmude (Mohamed) et al., 2009 Immunological Reviews, 228:58).? Know that the mutation in BTK leads to mankind's X linked agammaglobulinemia (XLA) and the chain immunodeficiency of mice X (Xid), The feature of both diseases be limited B- cell proliferation and decline antibody titer (Lin Dewo (Lindvall) et al., 2005 Immunological Reviews, 203:200).The compound action of the BTK in multiple cell types becomes for autoimmune disease Attractive target.BTK is related to the sequence homology with other Tec family kinases (ITK, Tec, ETK/BMX＆RLK/TXK).
In bone-marrow-derived lymphocyte, BTK is the Ca after B cell growth and B-cell receptor (BCR) joint2+Mobilize institute required (antiperspirant (Khan) et al., 1995 immunity (Immunity) 3:283；Zhan Niwei (Genevier) et al., 1997 clinical experiments are exempted from Epidemic disease (Clin.Exp.Immun.), 110:286), wherein think that BTK is located at Src family kinase (such as Lyn), under Syk＆PI3K Trip.It is all important (antiperspirant (Khan) that BTK has been shown for thymus dependent and thymus-independent 2 type antigen-reactive Et al., immunity (Immunity) 1995；3；283).In mastocyte, knock out, using BTK mice, the research carrying out and (breathe out him (Hata) et al., 1998 The Journal of Experimental Medicines (J.Exp.Med.), 187:1235；Schmidt (Schmidt) et al., 2009 Europe Journal of Immunology (Eur.J.Immun.), 39:3228) signal transduction, histamine release that BTK induces and thin are indicated in Fc ε RI The aborning effect of intracellular cytokine (such as TNF, IL-2 and IL-4).In platelet, BTK is for by making instead to collagen The signal transduction that GP VI (GPVI) receptor answered is carried out is important and shows promotion platelet aggregation and promote from fibre Dimension cell sample synovial cell generation cytokine (relax (Hsu) et al., 2013 immunologys communication (Immun.Letters), and 150: 97).In unicellular and macrophage, acting on of BTK is called in the signal transduction of Fc γ RI induction and can also be Play a role in the cytokine reaction (including TLR2, TLR4, TLR8＆TLR9) of Toll-like receptor induction (Huo Wude (Horwood) et al., 2003 The Journal of Experimental Medicines (J.Exp.Med.), 197:1603；Huo Wude (Horwood) et al., 2006 Journal of Immunology (J.Immunol.), 176:3635；Jefferson Pérez moral San Diego (PerezdeDiego) et al., 2006 anaphylaxis are clinical Immunology (Allerg.Clin.Imm.), 117:1462；Many Ilyushins (Doyle) et al., 2007 journal of biological chemistry (J.Biol.Chem.), 282:36959；Ha Sang (Hasan) et al., 2007 immunologys (Immunology), 123:239；Suo Ke Hot watt (Sochorava) et al., 2007 blood (Blood), 109:2553；Lee (Lee) et al., 2008, journal of biological chemistry (J.Biol.Chem.), 283:11189).
Therefore, the suppression of BTK is expected to intervene the several important node of inflammatory reaction, and it is anti-that these nodes produce autoimmune The effective suppression answered.Due to be related to the activation of B- cell receptor, antibody-Fc acceptor interaction and GPVI receptors signal transduction this Class disease can be by being adjusted with BTK inhibitor for treating.BTK suppression is possible to simultaneously act on rising of autoimmune disease Beginning (by blocking BCR signal transduction) and effector phase, are (by cancelling FcR to macrophage, neutrophil cell, basophil Born of the same parents and the signal transduction of mastocyte).Additionally, by suppress osteoclast cell maturation block BTK by provide other benefit and Therefore mitigate the bone erosion related to rheumatoid arthritiss and overall destruction of joint.Suppression BTK is substantial amounts of below treatment In inflammatory and anaphylactic disease be useful-such as (but not limited to), rheumatoid arthritiss (RA), systemic lupus erythematosus (sle) (SLE), multiple sclerosis (MS) and I type allergy (such as allergic rhinitises, anaphylaxis conjunctivitises, atopic dermatitis, mistake Quick property asthma and systemic anaphylaxises).With regard to targeting BTK as inflammatory diseasess and autoimmune disorder and leukemia and pouring The summary of the treatment of bar tumor, referring to female and khaki (Uckun＆Qazi), 2010 iatrotechnics patent comments of experts (ExpertOpin.Ther.Pat.), 20:1457.Because BTK is in the letter that hematopoietic system cancer camber is expressed and BTK relies on Number transduction is considered imbalance in these cancers, thus BTK inhibitor be expected to become for B cell lymphoma/leukemia and its His neoplastic disease (such as (but not limited to) acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin′ses (non-Hodgkin ' s) lymphoma (NHL), small lymphocytic lymphoma (SLL) and Acute Meyloid sample Leukemia is (with regard to summary, referring to Ba Ji and Elias (Buggy＆Elias) 2012 Interaational summary (IntRevImmunol.)31:119) useful treatment).Generally speaking, BTK inhibitor provides the substantial amounts of inflammatory disease for the treatment of Disease and the strong method of immunological disorder and hematologic cancer.
Colony-stimulating factor 1 receptor (CSF-1R) is homodimer, the III level receptor cheese ammonia of FMS proto-oncogene coding Acid kinase.It is 972 transmembrane amino acid albumen, and its feature is extracellular ligand binding domain, single membrane-spanning domain (TM), nearly film domain (JM), two intracellular kinase domains (TK1 and TK2), are separated by Kinase insert Domain (KI) and c terminal domains, UniProt Entry (Entry) P07333 (Pa Teer (Patel) et al. 2009 current medical chemistry theme (CurrentTopicsinMedicinalChemistry)9:599).CSF-1 is attached on the extracellular domain of CSF-1R and is stably subject to Body dimerization, the signal transduction inducing the trans autophosphorylation of Intracellular domain and activating downstream cellular matter.CSF-1R avtive spot Micromolecular inhibitor blocks receptor autophosphorylation and subsequently blocks control macrophage survival, the signal of expression, propagation and differentiation.
CSF-1R adjusts unicellular survival, propagation and differentiation and macrophage migration (Pixley (Pixley) et al. 2004 cytobiologies are now seen (TRENDS in Cell Biology), and 14:628).The native ligand of CSF-1R is identified For CSF-1 and IL-34.CSF-1R (includes hemopoietic progenitor cell, tissue macrophages, does not become in bone marrow unicellular property lineage Ripe B cell) in expression, this point involved in RA mechanism of causing a disease that (Hamilton (Hamilton) 2008 immunology is natural Summary (Nature Reviews Immunology) 8:533).The activation of known CSF-1R (does not include, but not in substantial amounts of disease Be limited to, RA, Crohn disease (Chrohn ' s disease), ulcerative enteritis, ankylosing spondylitises and cancer) in play a role (support (Toh) et al. 2014 Arthritis and Rheumatisms (Arthritis＆Rheumatology) 66:2989；Hume (Hume) etc. People 2012 blood (Blood) 119:1810 and Campbell (Campbell) et al. 2000 leukocyte-biological magazine (Journal ofLeukocyte Biology)68:144).Native ligand, CSF-1 and IL-34 express in the synovial membrane camber of RA patient, and And the CSF-1 level in the serum and synovial fluid of RA patient raises, and CSF-1 level (Falstein related to disease activity Et al. (Firestein) 1988 The Journal of Experimental Medicines (Journal of Experimental Medicine) 168:1573；River Control (Kawaji) et al. 1995Nippon Ika Daigaku Zasshi 62:260；This Na Wei of bearing of Ritchlin et al. 1994 Sub- Journal of Immunology (Scand.J.Immunol.) 40:292；Bamboo well (Takei) et al. 2000 Journal of Immunologies (J.Rheumatol.)27:894；Yellow (Hwang) et al. 2012 arthritis researchs and treatment (Arthritis Research＆ Therapy)14:R14 and He Meier (Chemel) et al. 2012 rheumatism yearbook (Ann.Rheum.Dis.) 71:150).
Fc γ RI, IIa and IIIa of monocell expressing elevated levels derived from RA patient, increases CD14 and oxygen is free Base, and reduce HLA-DR (formal little slender bamboo former (Shinohara) et al. 1992 rheumatism magazine (J.Rheumatol.) 19:211).Can be The CSF-1 of in vitro and in vivo restructuring produces this unicellular phenotype (wiener (Weiner) et al. 1994 cancer research (Cancer Res.)54:4084).Therefore, CSF-1 can drive raising, break up and surviving of RA synovial macrophages, and Myeloid progenitor cells Local proliferation.Additionally, CSF-1 makes macrophage be ready to is TNF and other cytokines preferably express (orchid fickle in love (Hanamura) 1997 immunopharmacologies (Immunopharmacology) 37:15).It has been proposed that CSF-1R participation is chronic The positive feedback loop of inflammation, wherein macrophages secrete induce TNF and IL-1 of the stromal cell expression of CSF-1, lead to huge biting Cell expand further and TNF and IL-1 other expression (Hamilton (Hamilton) 1993 lancet (Lancet) 342:536).
It is reported that CSF-1 deficient mice has resistance to Collagen-Induced Arthritis, and in the mouse model of CIA, show Show that CSF-1 makes disease aggravation, but the anti-CSF-1 antibody of neutralization makes amelioration of disease, and (Campbell (Campbell) et al. 2000 is white Cytobiology magazine (Journal of Leukocyte Biology) 68:144).Anti- CSF-1R monoclonal antibody is shown Going out in 2 different animal models of RA is effective (support et al. 2014 Arthritis and Rheumatism (Arthritis＆ Rheumatology)66:2989).Micromolecular inhibitor GW2580 shows the generation (health of the TNF of LPS induction in suppression mice Prestige (Conway) et al. 2005PNAS 102:16078).Additionally, there are several with regard to non-selective small molecule CSF-1R inhibitor Show that (handkerchief Buddhist nun's melon (Paniagua) et al. 2006 clinics are ground for the report of the effectiveness in arthritic preclinical disease model Study carefully magazine (J.Clin.Invest.) 116:2633；Kang Wei (Conway) et al. 2008 pharmacologys and experimental therapeutic magazine (J.Pharmacol.Exp.Ther.)326:41；Wild (Ohno) et al. greatly 2008 European Journal of Immunologies (Eur.J.Immunol.)38:283；Handkerchief Buddhist nun's melon (Paniagua) et al. 2010 arthritis research therapeuticss (Arthritis Res.Ther.)12:R32 and Ma Dan (Madan) et al. 2012 Journal of Immunologies (J.Imuunol.) 189:4123).
The related macrophage of tumor is related to the poor prognosis in various cancers and promotion that participate in angiogenesis, invades Enter and shift (objective case (Bingle) et al. 2002 pathology magazine (J.Pathol.) 196:254；Ripple rad (Pollard) 2004 Cancer summarizes (Nat.Rev.Cancer) 4 naturally:71 and Louis (Lewis) et al. 2006 cancer researches (Cancer Res.) 66:605).The CSF-1 deficient mice with MMTV-PyMT transgenic tumor shows macrophage recruitment minimizing and tumor The speed advancing to transfer declines (Louis (Lewis) et al. 2006 cancer researches (Cancer Res.) 66:605).Show Macrophages infiltration is repaired in the breast epithelium expression of CSF-1 and metastatic tumo(u)r vascular system is characterized, and has shown vascular The induction of system is (woods (Lin) et al. 2001 The Journal of Experimental Medicines being adjusted by the related macrophage of tumor (J.Exp.Med.)193:727).Human breast tumors' xenograft have CSF-1 antisense oligonucleotide (ODN-196) or SiRNA CSF-1siRNA and FMS siRNA) mice in lower target protein suppress breast tumor growth (than this Gas (Biswas) et al. 2008 Journal of Immunologies (J.Immunol.) 180:2011).In breast carcinoma the expression of FMS with bad Survivability (Krueger (Kluger) et al. 2004 Clinical Cancer Research related with the increase of tumor size (Clin.CancerRes.)10:173；Woods (Lin) et al. 2001 The Journal of Experimental Medicines (J.Exp.Med.) 193:727；Happy Et al. (Yee) 2000 anticancers research (Anticancer Res.) 20:4379).
CSF-1 antibody has shown that treatment potentiality on treatment solid tumor.Used in MCF-7 mammary gland xenograft mouse model In anti-CSF01Fab antibody carry out treatment suppression tumour growth (Borrow Si (Paulus) et al. 2006 cancer researches (Cancer Res.)66:4349).The micromolecular inhibitor Ki20227 of CSF-1R, the bone resorption in suppression metastasis model is destroyed (big Wild (Ohno) 2006 molecule cancer therapy (Mol.Cancer Ther.) 5:2634).In single research, also show CSF-1 produces and the osteoclast of TAM can be promoted to generate and promote tumor related bone dissolving (poplar (Yang) 2002 bone and joint (J.Bone Joint Surg.Br.) 84 rolls up in surgical magazine Britain:452).
Therefore the suppression of CSF-1 is likely to be of therapeutic value in treatment autoimmune disease and cancer.
The general introduction of the present invention
In the first embodiment, the invention provides having the compound of chemical formula (I)
Wherein
U is CR1Or N；
X is CR2Or N；
Y is CR3Or N；
Z is CR4Or N；
R1It is independently H or deuterium；
R2It is H, deuterium, optionally substituted (C1-C3) alkyl, or CF3；
R3It is H, deuterium or optionally substituted (C1-C3) alkyl；
R4It is H or deuterium；
R5It is-R501-L-R502Wherein
R501It is key ,-O- ,-OCH2- or optionally substituted (C1-C3) alkylidene,
L be-C (=O)-,-CH2N (H) C (=O)-,-N (H) C (=O)-or-N (H) S (O)2；Or
L is key and R502It is-CN；Or
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted saturation or fractional saturation Heterocyclic radical or optionally substituted saturation or fractional saturation (C3-C7) cycloalkyl and L2It is key ,-CH2N(Ra)-、- CH2N(Ra)C(O)-、-N(Ra)C(O)-、-N(Ra)S(O)2- or-N (Ra)-；Or
L1It is the heterocyclic radical of saturation or fractional saturation, this heterocyclic radical comprises one or more hetero atoms, wherein at least one Individual hetero atom is nitrogen and L2It is key, C (O) or-S (O)2-；
R502It is H, CF3, OH, optionally substituted (C1-C6) alkyl, optionally substituted thiazolinyl, optionally substituted alkynes Base, CN or optionally substituted (C3-C6) cycloalkenyl group；
R6It is optionally substituted (C1-C6) alkyl, optionally substituted (C3-C12) cycloalkyl, optionally substituted benzene Base, optionally substituted heteroaryl or optionally substituted heterocyclic radical；Or
R6It is-R601-R602, wherein R601Be attached to-N (H)-and
R601It is optionally substituted heteroaryl；
R602It is N (Ra)2, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl or optionally The heterocyclic radical replacing；And
RaIt is independently H or optionally substituted (C1-C6) alkyl；
Its condition is this compound is not 2- (3- { 8- [5- (morpholine -4- carbonyl)-pyridine -2- base amino]-imidazoles [1,2- A] pyridine -6- base }-phenyl)-N- (the fluoro- 4- hydroxy-4-methyl of 5,5,5- tri--amyl- 2- alkynyl)-acetamide.
In a second embodiment, the present invention provides the compound according to this first embodiment, wherein
U is CR1Or N；
X is CR2Or N；
Y is CR3Or N；
Z is CR4Or N；
R1It is independently H or deuterium；
R2It is H, deuterium, optionally substituted (C1-C3) alkyl or CF3；
R3It is H, deuterium or optionally substituted (C1-C3) alkyl；
R4It is H or deuterium；
R5It is-R501-L-R502Wherein
R501It is key ,-O- ,-OCH2- or optionally substituted (C1-C3) alkylidene,
L be-C (=O)-,-CH2N (H) C (=O)-,-N (H) C (=O)-or-N (H) S (O)2；Or
L is key and R502It is-CN；Or
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted saturation or fractional saturation Heterocyclic radical or optionally substituted saturation or fractional saturation (C3-C6) cycloalkyl and L2It is key ,-CH2N(Ra)-、- CH2N(Ra)C(O)-、-N(Ra)C(O)-、-N(Ra)S(O)2- or-N (Ra)-；Or
L1It is the heterocyclic radical of saturation or fractional saturation, this heterocyclic radical comprises one or more hetero atoms, wherein at least one Individual hetero atom is nitrogen and L2It is key, C (O) or-S (O)2-；
R502It is H, optionally substituted thiazolinyl, optionally substituted alkynyl, CN or optionally substituted (C3-C6) cyclenes Base；
R6It is optionally substituted (C1-C6) alkyl, optionally substituted (C3-C12) cycloalkyl, optionally substituted benzene Base, optionally substituted heteroaryl or optionally substituted heterocyclic radical；And
RaIt is independently H or optionally substituted (C1-C6) alkyl.
In the third embodiment, the present invention provides the compound according to any one of previous embodiment, wherein
L be-C (=O)-,-CH2N (H) C (=O)-,-N (H) C (=O)-or-S (O)2；And R502It is H ,-CH=CH2 Or-C ≡ CH；Or
L is key and R502It is-CN；Or
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted saturation or fractional saturation (C3-C6) cycloalkyl and L2It is-CH2N(Ra)-、-CH2N(Ra)C(O)-、-N(Ra)C(O)-、-N(Ra)S(O)2- or-N (Ra)-；Or
L1It is optionally substituted heteroaryl, optionally substituted nitrogen heterocyclic heptyl, optionally substituted azetidin Alkyl, optionally substituted morpholinyl, optionally substituted oxazepine cycloheptyl alkyl, optionally substituted piperidyl, optionally Pyrrolidinyl, optionally substituted tetrahydrofuran base or optionally substituted THP trtrahydropyranyl that ground replaces, and L2It is key, C Or-S (O) (O)2-.
In the fourth embodiment, the present invention provides the compound according to any one of previous embodiment, wherein R6It is Optionally substituted (C1-C6) alkyl, optionally substituted phenyl, optionally substituted bicyclo- [1.1.1] pentyl ester, optionally take 1,2,4 di azolies in generation, optionally substituted pyrazolyl, optionally substituted pyridazinyl, optionally substituted pyridine radicals, 4, 5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one, 3,4- dihydroquinoline -2 (1H) -one, 2H- benzo [b] [1,4] piperazine -3 (4H) -one or 6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine base.
In the 5th embodiment, the present invention provides the compound according to any one of previous embodiment, wherein R6Appoint Selection of land is substituted by one or more substituents, and this or these substituent group is independently selected from (C1-C3) alkyl, (C1-C3) alcoxyl Base, optionally substituted imidazolone or morpholinyl.
In the sixth embodiment, the present invention provides the compound according to any one of previous embodiment, wherein-L- R502Form-CN ,-CH2N (H) C (=O) CH=CH2,-C (=O) CH=CH2,-N (H) C (=O) CH=CH2,-N (H) CN or- S(O)2CH=CH2.
In the 7th embodiment, the present invention provides the compound according to any one of previous embodiment, wherein this change Compound is
N- (3- (8- ((4- morphlinophenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) benzyl Base) acrylamide；
N- (3- (8- (bicyclo- [1.1.1] amyl- 1- base amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- Base) benzyl) acrylamide；
N- (3- (8- (bicyclo- [1.1.1] amyl- 1- base amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- Base) phenyl) acrylamide；
1- (3- (8- ((3,4- Dimethoxyphenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
8- ((5- (1- acryloyl pyrrolidin-3-yl) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia Base) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one；
1- (3- (8- ((4- morpholino pyridine -2- base) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((5- methoxyl group pyridazine -3- base) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyridine -5- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
N- (2- (8- (bicyclo- [1.1.1] amyl- 1- base amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- Base) phenyl) acrylamide；
1- ((3R) -3- (8- ((3,4- Dimethoxyphenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- ((3S) -3- (8- ((3,4- Dimethoxyphenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
8- ((6- (1- Antiepilepsirin -3- base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro - 1H- benzo [b] azatropylidene -2 (3H) -one；
N- (3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) phenyl) acrylamide；
N- (3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) benzyl) acrylamide；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
7- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -3,4- two Hydrogen quinoline -2 (1H) -one；
6- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -2H- benzo [b] [1,4] piperazine -3 (4H) -one；
8- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) -4,5- two Hydrogen -1H- benzo [b] azatropylidene -2 (3H) -one；
(S) -8- ((6- (1- acryloyl pyrrolidin-3-yl) imidazo [1,2-a] pyrazine -8- base) amino) -4,5- dihydro - 1H- benzo [b] azatropylidene -2 (3H) -one；
(R) -8- ((6- (1- acryloyl pyrrolidin-3-yl) imidazo [1,2-a] pyrazine -8- base) amino) -4,5- dihydro - 1H- benzo [b] azatropylidene -2 (3H) -one；
(S)-N- (3,4- Dimethoxyphenyl) -6- (1- (ethenesulfonyl) pyrrolidin-3-yl)-[1,2,4] triazole [1, 5-a] pyrazine -8- amine；
1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines - 1- yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridazine -3- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- (methylamino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- Ketone；
1- (3- (8- ((2- methoxy ethyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidin-1-yl) Propyl- 2- alkene -1- ketone；
1- (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone；
(S) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
(R) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridin-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) piperidines -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridin-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine - 1- yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((3- isopropyl -1,2,4- diazole -5- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) piperidin-1-yl) propyl- 2- alkene -1- ketone；
N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) cyclohexyl) acrylamide；
N- ((1S, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) methyl)-[1,2,4] triazole [1,5-a] pyridine -6- Base) cyclohexyl) acrylamide；
1- (3- (8- ((3- methyl isophthalic acid, 2,4- diazole -5- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Piperidin-1-yl) propyl- 2- alkene -1- ketone；
N- ((1S, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) cyclohexyl) cyanamide；
3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- Formonitrile HCN；
3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine - 1- formonitrile HCN；
1- (4- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) benzene Base) -3- Methylimidazole. quinoline -2- ketone；
3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine - 1- formonitrile HCN；
N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) cyclopenta) acrylamide；
N- ((1S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Cyclopenta) acrylamide；
3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] Pyridine -6- base) piperidines -1- formonitrile HCN；
(S) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
(R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
(S) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
(R) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
(S) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone；
1- ((rattle away 3- by 8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino) imidazo [1,2-b] Piperazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；Or
(R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone.
In the 8th embodiment, the present invention provides the compound according to any one of previous embodiment, wherein
R5It is-R501-L-R502Wherein
R501It is key；
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is (the C of optionally substituted saturation or fractional saturation3-C7) cycloalkyl and L2It is key-CH2N(Ra)C (O)-or-N (Ra)C(O)-；And
R502It is H, CF3, OH, optionally substituted (C1-C6) alkyl, optionally substituted thiazolinyl, optionally substituted alkynes Base, CN or optionally substituted (C3-C6) cycloalkenyl group.
In the 9th embodiment, the present invention provides the compound according to any one of previous embodiment, wherein
R6It is optionally substituted (C1-C6) alkyl, optionally substituted (C3-C12) cycloalkyl, optionally substituted benzene Base, optionally substituted pyrazolyl, optionally substituted 6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine base, optionally take 4,5,6,7- tetrahydro-pyrazole [1,5-a] pyrazinyl in generation；Or
R6It is-R601-R602, wherein R601Be attached to-N (H)-and
R601It is optionally substituted pyrazolyl or optionally substituted pyridine radicals；
R602It is N (Ra)2, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally take The azetidinyl in generation, optionally substituted morpholinyl, optionally substituted piperidyl or optionally substituted Pentamethylene oxide. Base.
In the tenth embodiment, the present invention provides compound according to claim 9, wherein R1It is H.
In the 11st embodiment, the present invention provides the compound according to any one of previous embodiment, and wherein X is N or CR2, wherein R2It is H, optionally substituted (C1-C3) alkyl or CF3.
In the 12nd embodiment, the present invention provides the compound according to any one of previous embodiment, wherein R3 It is H, deuterium or optionally substituted (C1-C3) alkyl.
In the 13rd embodiment, the present invention provides the compound according to any one of previous embodiment, and wherein U is CH.
In the 14th embodiment, the present invention provides the compound according to any one of previous embodiment, and wherein X is N.
In the 15th embodiment, the present invention provides the compound according to any one of previous embodiment, wherein should Compound is
4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2- first Base butyl- 2- alcohol；
6- cyclohexyl-N- (1- (tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -8- amine；
6- cyclohexyl-N- (1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles -4- base)-[1,2,4] Triazole [1,5-a] pyrazine -8- amine；
6- cyclohexyl-N- (1- (oxetanes -3- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine - 8- amine；
(1R, 4R) -4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) Hexalin；
(1s, 4s) -4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) Hexalin；
6- cyclohexyl-N- (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
(6- cyclohexyl-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclopenta-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclohexyl-N- (1- isopropyl -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- (4,4- Dimethylcyclohexyl)-N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine - 8- amine；
N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- ((1R, 4R) -4- methylcyclohexyl)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -8- amine；
N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- ((1S, 4S) -4- methylcyclohexyl)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -8- amine；
N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- ((1R, 4R) -4- (trifluoromethyl) cyclohexyl)-[1,2,4] triazole [1, 5-a] pyrazine -8- amine；
N- (6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine；
6- cyclohexyl-N- (5- methyl -4,5,6,7- tetrahydro-pyrazole [1,5-a] pyrazine -2- base)-[1,2,4] triazole [1,5- A] pyridine -8- amine；
6- cyclopenta-N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclopenta-N- (5- methyl -4,5,6,7- tetrahydro-pyrazole [1,5-a] pyrazine -2- base)-[1,2,4] triazole [1,5- A] pyridine -8- amine；
1- (4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) piperazine Pyridine -1- base) ethyl ketone；
4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl)-N- first Phenylpiperidines -1- Methanamide；
(1S, 3S) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) Hexalin；
(1R, 3R) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) Hexalin；
(1R, 3S) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) Hexalin；
(1S, 3R) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) Hexalin；
(1R, 3R) -3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Hexalin；
1- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2- first Base propan-2-ol；
N- (6- cyclopenta-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine；
1- (6- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) pyridin-3-yl) piperidines -4- alcohol；
6- cyclohexyl-N- (1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine - 8- amine；
(1S, 4S)-ethyl 4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrrole Azoles -1- base) naphthenic acid ester；
6- cyclopenta-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine； Or
6- cyclohexyl-N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine.
In the 16th embodiment, the method that the present invention provides treatment disease, the method is included to its patient in need Apply the compound of the therapeutically effective amount according to any one of previous embodiment.
In the 17th embodiment, the present invention provides the method according to the 16th embodiment, and wherein this disease is class Rheumatic arthritis, juvenile rheumatoid arthritiss, osteoarthritis, Crohn disease (Crohn ' sdisease), inflammatory bowel, Irritable bowel syndrome, ulcerative enteritis, psoriasis arthropathica, psoriasises, ankylosing spondylitises, interstitial cystitiss, asthma, Systemic lupus erythematosus (sle), lupus nephritis, B cell chronic lymphocytic lymphoma, multiple sclerosis, chronic lymphocytic Property leukemia, small lymphocytic lymphoma, lymphoma mantle cell, B cell non-Hodgkin lymphoma, activation B cell sample more Unrestrained property large B cell lymphoid tumor, multiple spinal cord tumor, diffusivity large B cell lymphoid tumor, follicular lymphoma, hairy cell leukemia Or LBL.
In the 18th embodiment, the present invention provides the test kit of the product comprising to pack, and the product of this packaging comprises many Plant component, these components are given for treating together with the compound according to the first to the 15th any one of embodiment Autoimmune is disorderly.
In the 19th embodiment, the present invention provides the test kit according to the 18th embodiment, wherein this packaging Product comprise the compound described in the first to the 15th embodiment and operation instructions.
In the 20th embodiment, the present invention provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises to arrive according to first Compound described in 15th any one of embodiment, and one or more pharmaceutically acceptable excipient.
Detailed description of the Invention
Protein kinase is the wide variety of classification having more than 500 kinds of enzymes, and it includes oncogene, somatomedin The related kinases of receptor, signal transduction intermediate, apoptosis and cyclin-dependent kinase.They are responsible for phosphate group It is transferred to specific tyrosine, serine or threonine amino acid residues, and broadly divided as the result of their substrates Class is tyrosine and serine/threonine kinase.
These protein kinases represent big protein familieses, and these protein are in diversified cell processes Adjust and play central role in the maintenance with cell function.The nonrestrictive list of the part of these kinases includes：Non- receptor Tyrosine kinase, such as Tec family (BTK, ITK, Tec, ETK/BMX＆RLK/TXK), Janus kinase families (Jak1, Jak2, Jak3 and Tyk2)；Merge kinases, such as BCR-Abl, focal adhesion kinase (FAK), Fes, Lck and Syk；Receptor tyrosine kinase, For example, EGF-R ELISA (EGFR), platelet-derived growth factor receptor kinase (PDGF-R), stem cell factor Receptor kinase, c-kit, C-MET HGFr, c-Met and fibroblast growth factor acceptor, FGFR3；With silk ammonia Acid/threonine kinase, such as b-RAF, mitogen activated protein kinases (for example, MKK6) and SAPK2 β.In numerous disease Abnormal kinase activity is observed, described morbid state includes benign and malignant proliferative disorder and due to immune system in state The disease that improper activation with nervous system leads to.The compounds of the present invention suppress the work of one or more protein kinase Property, and be therefore expected to be used for treating kinase mediated disease.
Bruton's tyrosine kinase (BTK) is nonreceptor tyrosine kinase, its many hematopoietic cells (include B cell, Platelet, mastocyte, basophilic granulocyte, eosinophilic granulocyte, macrophage and neutrophilic granulocyte and participation osteoclasia Osteoclast) in immunity receptor signal (BCR, Fc ε R, Fc γ R, DAP12, Dectin-1, GPVI etc.) in there is crucial work With (referring to Bruner (Brunner) et al., 2005 histologys and histopathology (Histol.Histopathol.), 20: 945, Mo Hanmude (Mohamed) et al., 2009 Immunological Reviews, 228:58).Known mutation in BTK leads to mankind X even Lock agammaglobulinemia (XLA) and the chain immunodeficiency of mice X (Xid), the feature of both diseases is limited B- Cell proliferation and decline antibody titer (Lin Dewo (Lindvall) et al., 2005 Immunological Reviews, 203:200).Multiple The compound action of the BTK in cell type becomes the attractive target for autoimmune disease.BTK with other The sequence homology that Tec family kinase (ITK, Tec, ETK/BMX＆RLK/TXK) has is related.
In bone-marrow-derived lymphocyte, the Ca2+ mobilization after BTK is B cell growth and B-cell receptor (BCR) joint is musted (antiperspirant (Khan) et al., 1995 immunity (Immunity) 3 needing:283；Zhan Niwei (Genevier) et al., 1997 clinical experiments Immune (Clin.Exp.Immun.), 110:286), wherein think that BTK is located at Src family kinase (such as Lyn), Syk＆PI3K Downstream.It is all important (antiperspirant that BTK has been shown for thymus dependent and thymus-independent 2 type antigen-reactive (Khan) et al., immunity (Immunity) 1995；3；283).In mastocyte, knock out, using BTK mice, the research carrying out (breathe out his (Hata) et al., 1998 The Journal of Experimental Medicines (J.Exp.Med.), 187:1235；Schmidt (Schmidt) et al., 2009 European Journal of Immunologies (Eur.J.Immun.), 39:3228) signal transduction, histamine that BTK induces are indicated in Fc ε RI Release and the aborning effect of cytokine (such as TNF, IL-2 and IL-4).In platelet, BTK is for by glue The signal transduction that former GP VI (GPVI) receptor made a response is carried out be important and show promotion platelet aggregation and (relax (Hsu) et al., 2013 immunology communications to promote fibroblast sample synovial cell to produce cytokine (Immun.Letters), 150:97).In unicellular and macrophage, the signal transduction acting on Fc γ RI induction of BTK In called and can also send out in the cytokine reaction (including TLR2, TLR4, TLR8＆TLR9) of Toll-like receptor induction The effect of waving (Huo Wude (Horwood) et al., 2003 The Journal of Experimental Medicines (J.Exp.Med.), 197:1603；Huo Wude (Horwood) et al., 2006 Journal of Immunologies (J.Immunol.), 176:3635；Jefferson Pérez moral San Diego (PerezdeDiego) Et al., 2006 anaphylaxis clinical immunologies (Allerg.Clin.Imm.), 117:1462；Many Ilyushins (Doyle) et al., 2007 is raw Thing The Chemicals (J.Biol.Chem.), 282:36959；Ha Sang (Hasan) et al., 2007 immunologys (Immunology), 123:239；Suo Kerewa (Sochorava) et al., 2007 blood (Blood), 109:2553；Lee (Lee) et al., 2008, raw Thing The Chemicals (J.Biol.Chem.), 283:11189).
Therefore, the suppression of BTK is expected to intervene the several important node of inflammatory reaction, and it is anti-that these nodes produce autoimmune The effective suppression answered.Due to be related to the activation of B- cell receptor, antibody-Fc acceptor interaction and GPVI receptors signal transduction this Class disease can be by being adjusted with BTK inhibitor for treating.BTK suppression is possible to simultaneously act on rising of autoimmune disease Beginning (by blocking BCR signal transduction) and effector phase, are (by cancelling FcR to macrophage, neutrophil cell, basophil Born of the same parents and the signal transduction of mastocyte).Additionally, by suppress osteoclast cell maturation block BTK by provide other benefit and Therefore mitigate the bone erosion related to rheumatoid arthritiss and overall destruction of joint.Suppression BTK is substantial amounts of below treatment In inflammatory and anaphylactic disease be useful-such as (but not limited to), rheumatoid arthritiss (RA), systemic lupus erythematosus (sle) (SLE), multiple sclerosis (MS) and I type allergy (such as allergic rhinitises, anaphylaxis conjunctivitises, atopic dermatitis, mistake Quick property asthma and systemic anaphylaxises).With regard to targeting BTK as inflammatory diseasess and autoimmune disorder and leukemia and pouring The summary of the treatment of bar tumor, referring to female and khaki (Uckun＆Qazi), 2010 iatrotechnics patent comments of experts (ExpertOpin.Ther.Pat.), 20:1457.Because BTK is in the letter that hematopoietic system cancer camber is expressed and BTK relies on Number transduction is considered imbalance in these cancers, thus BTK inhibitor be expected to become for B cell lymphoma/leukemia and its His neoplastic disease (such as (but not limited to) acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin′ses (non-Hodgkin ' s) lymphoma (NHL), small lymphocytic lymphoma (SLL) and Acute Meyloid sample Leukemia is (with regard to summary, referring to Ba Ji and Elias (Buggy＆Elias) 2012 Interaational summary (IntRevImmunol.)31:119) useful treatment).Generally speaking, BTK inhibitor provides the substantial amounts of inflammatory disease for the treatment of Disease and the strong method of immunological disorder and hematologic cancer.
All kinases combine a common molecule, ATP, and therefore have similar binding pocket in structure (binding pocket).Therefore, one of the challenge for any kinase inhibitor is, due to the homology of binding pocket, this A little kinases tend to suppress more than one kinases.For example, D-82041 DEISENHOFEN, a kind of kinase inhibitor mixing characterizing well Have shown that at least 253 kinds human kinase protein groups of suppression and have<The k of 3MdKinases (referring to Nature Biotechnol (Nature Biotechnology), 208,26, p.127).Additionally it is known that several kinase inhibitor put on market suppresses Exceed a kind of purpose kinases, such as imatinib (Glivec) targeting ABL, ARG, PDGFR- α/β and c-KIT Kinases, Sorafenib (Nexavar) targeting B-RAF, VEGFR, PDGFR- α/β, FLT3 and c-KIT and Buddhist nun of relaxing For Buddhist nun's (SUTENT) targeting VEGFR, PDGFR, CSF-1R, FLT3 and c-KIT (comment drug discovery naturally (Nature Reviews Drug Discovery)2011,10,111).
When being known for use as Drug therapy, some kinases in human kinase protein group for the suppression have undesirable effect. For example, a large amount of kinases targeting have involved and have played a role in composing in the cardiac toxicity of kinase inhibitor in the market.This A little kinases include but is not limited to VEGFR2, PI3K, AKT, PDGFR- α/β, AMPK, GSK3, ERKs, CDK2, Aurora, PLK, JNK、CAMKII<PDK1、mTOR、LKB1、CAMKK、MEK1/2、PKA、PKCα、RAF1、B-RAF、EGFR、ERBB2、c-Kit、 ABL, ARG, JAK2, FAK, DMPK, LTK, ROCK, LKB1, LDB3, PIM, GRK2, GRK5, ASK1 and PTEN are (referring to naturally comprehensive State drug discovery (Nature Reviews DrugDiscovery) 2011,10:111).From the kinase inhibitor put on market An example be, in the clinical trial with Sutent, find patient suffer from hypertension risk increase (referring to lancet (TheLancet)2006,368:1329；And Journal of Clinical Oncology (J.Clin.Oncol.) 2009,27:3584).Subsequently Show although PDGFR and VEGFR may play a role with regard to the research of mechanism for the hypertension raising, but it is sharp to miss the target Enzyme level, such as AMPK are it is also possible to the risk of hypertension of suffering from that may consequently contribute to Sutent increases (up-to-date hypertension report (Curr.Hypertens.Rep.)2011,13:436).Additionally, there is submitted patent application US 2011/0212461, It is a kind of method with regard to predicting cardiac toxicity, based on a series of activity with respect to kinases, these kinases include the method： KIT, FYN, PDGFR β, FGR, LCK, Ephrin receptor B2, FRK, ABL1, PDGFR1 α, HCK, ABL2, LYN, ZAK, YES1, MAP4K4, PKN1, BRAF, DDR2, MAP4K5 and STK24.Therefore, there is kinase inhibitor (Btk or CSF-1R of selectivity spectrum Kinases) identification be desirable to.The suppression that the compound of the present invention exceedes other kinases for Btk or CSF-1R is selectivity 's.
Many kinases, either to have been observed that participation is related to countless for receptor or nonreceptor tyrosine kinase or S/T kinases The cell signalling passage of pathological condition (including immunomodulating, inflammation or proliferative disorder such as cancer).
Many autoimmune disease and the disease related to chronic inflammatory disease and acute reaction are all thin with one or more The generation of excessive or imbalance of intracellular cytokine or activity are associated.
These compounds of the present invention are useful on treating following disease：Rheumatoid arthritiss, asthma, anaphylaxis Asthma, osteoarthritis, juvenile arthritises, ankylosing spondylitises, eye disorders, interstitial cystitiss, cancer, solid tumor, meat Tumor, fibrosarcoma, osteoma, melanoma, retinoblastoma, rhabdomyosarcoma, glioblastoma, neuroblastoma, Teratocarcinoma, allergy, the hyperkinetic dyskinesia, super quick pneumonia, hypertension, the hypokinesias dyskinesia, master Tremulous pulse and peripheral arterial tumor, hypothalmus-pituitary-adrenal axis assessment, dissection of aorta, Arterial Hypertention, arteriosclerosis, sound Arteries and veins fistula, ataxia, spinocerebellar degeneration, streptococcus myositis, cerebellum structural damage, subacute sclerosing panencephalitises, faint, the heart Vascular system syphilis, systemic anaphylaxises, systemic inflammatory response syndrome, whole body morbidity type Rheumatoid Arthritis, T Cell or FABALL, telangiectasis, thromboangiitis obliteranss, transplanting, wound/bleeding, type III allergy, IV type Super quick, unstable angina pectoriss, uremia, urine pyemia, urticaria, valvular heart disease, varicosis, vasculitises, vein Disease, phlebothrombosises, room quiver, viral and fungoids inflammation, viral encephalitiss/aseptic meningitiss, vital bloodthirsty Cell Syndrome (vital-associated hemaphagocytic syndrome), Wernicke-Korsakoff syndrome, Wilson's disease, the xenograft rejection reaction of any organ or tissue, heart transplant rejection, hemachromatosises, hemodialysis, Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura, bleeding, idiopathic pulmonary fibrosises, antibody-mediated cell Toxicity, weakness, infantilism spinal muscular atrophy, aorta inflammation, A type influenza, ionizing radiation exposure, iridocyclitises/Fructus Vitis viniferae Film inflammation/optic neuritis, juvenile form Duchenne-Arandisease, lymphoma, spinal cord tumor, leukemia, malignant ascite, hematopoietic system cancer, Diabetogenous disease (such as insulin dependent diabetes mellitus (IDDM) type glaucoma, diabetic retinopathy or microangiopathy), sickle Shape cell anemia, chronic inflammatory disease, glomerulonephritiies, graft-rejection, Lyme disease, Xi Peier forest-road (vonHippel- Lindau) disease, pemphiguss, Paget (Paget ' s disease), fibrosiss, sarcoidosises, liver cirrhosis, thyroiditiss, height are viscous Degree syndrome, Osler Weber Rendu, chmnic. obstructive's pneumonopathy, (burn, wound, radiation, apoplexy, anoxia, ischemia, ovum Cardiotomy syndrome, eclamposia after syndrome after syndrome after nest hyperstimulation syndrome, perfusion, pump, myocardial infarction, pass through the moon Many, endometriosis, pulmonary hypertension, infant hemangioma or (herpes simplex, herpes zoster, human immunodeficiency Poison, parapoxviruses, protozoacide or toxoplasma cause) occur after inflammation) property fiber crops on asthma or edema, progressive core Numbness, primary pulmonary hypertension, X-ray therapy, Raynaud's phenomenon, Raynaud disease, refsum's disease, conventional narrow QRS mistake aroused in interest Speed, renal vascular hypertension, restrictive cardiomyopathy, sarcoma, senile chorea, Louis build senile dementia, shock, skin move Plant, skin change syndrome, eye or macular edema, neovascular eye diseases, scleritis, radial keratotomy, Fructus Vitis viniferae Syndrome, conjunctivitis, Si Te after the congenital little recessed, chronic retinal detachment of film inflammation, hyalitises, myopia, optic disc, laser therapy Graves disease, Eales'disease (Eales disease), retinopathy, macula lutea sexual involution, restenosiss, ischemia/reperfusion injury, Cerebral infarction, vascular occlusion, carotid obstructive disease, ulcerative colitiss, inflammatory bowel, irritable bowel syndrome, polyuria Disease (diabetes), diabetes (diabetes mellitus), insulin-dependent diabetes, anaphylactic disease, dermatitis sclerderm Disease, graft versus host disease, organ transplant rejection (including but not limited to bone marrow and solid organ rejection's reaction) and device The related acute or chronic immunologic derangement of official's transplanting, sarcoidosises, disseminated inravascular coagulation, mucocutaneous lymphnode syndrome, nephrotic syndrome, chronic Fatigue syndrome, Wei Genashi granulomatosis, anaphylactoid purpura, kidney microscope vasculitises (microscopic vasculitis Of the kidneys), chronic active hepatitiss, inflammatory shock, toxic shock syndrome, TSS, sepsis syndrome, cachexia, Diseases associated with inflammation, parasitic disease, acquired immune deficiency syndrome (AIDS), acute transverse myelitises, hungtington's chorea (Huntington's chorea), apoplexy, primary biliary cirrhosis, hemolytic anemia, malignant tumor, Addison's disease (Addison's disease), idiopathic Addison's disease, the polyadenous volume defect I type distributing and polyadenous volume defect II type, Shi Mi Special Cotard (Schmidt's syndrome), adult's (acute) respiratory distress syndrome, alopecia, alopecia areata, seronegativity are closed Section disease, arthrosiss, Lai Teer disease (Reiter's disease), psoriasis arthropathica disease, ulcerative colitis inflammatory arthrosiss, enteropathy Property synovitis, chlamydia, the yersinia arthrosiss related with Salmonella, atherosclerosis/tremulous pulse are athero- Hardening, atopic allergy, autoimmunity bullous diseases, pemphigus vulgarises, pemphigus foliaceuses, pemphigoid, line Shape IgA disease, autoimmune hemolytic anemia, Claire (Coombs) positive hemolytic anemias, acquired pernicious anemia, childhood Type pernicious anemia, peripheral blood vessel, peritonitis, pernicious anemia, myalgic encephalitis/myalgic encephalomyelitis, chronic skin glue Film candidiasiss, giant cell arteritises, primary sclerotic hepatitis, hidden source property autoimmune hepatitiss, acquired immunodeficiency Disease syndrome, acquired immunodeficiency relevant disease, hepatitis A, hepatitis B, hepatitis C, Xinier reservoir arrhythmia, HIV inflammation/HIV god Through sick, common multiple changing type immunodeficiency (common multiple changing type low gamma globulinemia), dilated cardiomyopathy, female sterility Disease, ovarian function failure, premature ovarian failure, fibrotic lung disease, chronic wound care, hidden source property FA, inflammation The related interstitial lung disease of interstitial lung disease after disease, interstitial pneumonia, pneumocystis carinii pneumonia, pneumonia, connective tissue disease, Between the related interstitial lung disease of mixed connective tissue disease, associated pulmonary diseases, Sjogren's syndrome, rheumatoid arthritiss correlation The related lung of the related pneumonopathy of the related pneumonopathy of matter pneumonopathy, systemic lupus erythematosus (sle), dermatomyositiss/polymyositiss, sjogren syndrome The related pneumonopathy of the related pneumonopathy of disease, ankylosing spondylitises, vasculitises lung Diffuse Diseases, haemosiderosis, medicine The interstitial lung disease of induction, radioactivity fiber disease, bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyte Interstitial lung disease, gouty arthritises, lupoid hepatitis, 1 type lupoid hepatitis (warp after wellability pneumonopathy, inflammation Allusion quotation autoimmune or lupoid hepatitis), 2 type auto immune hepatitis (anti-LKM antibody hepatitis), autoimmune mediation hypoglycemia Disease, Type B insulin resistant are disorderly with acanthosis nigricanss, the other adenasthenia disease of the thyroid acute immune related to organ transplantation The disorderly Chronic immune disorder related to organ transplantation, osteoarthritis, primary sclerosing cholangitiss, 1 psoriasis pustulosa, 2 type silver bits Disease, idiopathic leukopenia, autoimmune neutropenia, nephropathy NOS, glomerulonephritiss, kidney show Vasculitises (microscopic vasculitis of the kidneys), Lyme disease, discoid lupus erythematosus, spy under micro mirror Send out property male infertility or NOS, sperm autoimmune, multiple sclerosis (all hypotypes), sympathetic ophthalmia, be secondary to connective The pulmonary hypertension of tissue disease, acute and chronic pain (pain of multi-form), Goodpasture's syndrome (Goodpasture's syndrome), the pulmonary of polyarteritis nodosa, acute rheumatic fever, poker back, Still's disease, Sjogren's syndrome, sjogren syndrome, Takayasu's disease pulseless disease/arteritis, autoimmune thrombocytopenia, toxicity, shifting Plant and be related to improper angiogenesis disease (for example diabetic retinopathy, retinopathy of prematurity, due to age-phase Infant hemangioma in the choroidal neovascularization that leads to of degeneration of macula closed and the mankind).In addition, these compounds with It is useful in lower disorder treatment：Such as ascites, hydrops and exudate, damage including such as macular edema, cerebral edema, acute lung Wound, adult respiratory distress syndrome (ARDS), proliferative lesion (as restenosiss), fibrosis lesion are (as liver cirrhosis and tremulous pulse medicated porridge Sample harden), mesangial cell proliferative pathological changes (as diabetic nephropathy, malignant nephrosclerosises, thrombotic microangiopathy syndrome and Glomerulopathy), angiogenesis of cardiac muscle, coronary artery and brain is collateral, ischemic limb angiogenesis generation, ischemia/reperfusion injury, Peptic ulcer pylori relevant disease, the disorder of viral-induced angiogenesis, eclamposia, menorrhagia, ram's horn be warm, rubescent, Neovascular glaucoma and retinopathy are (as related to diabetic retinopathy, neonate retinopathy or age Those of degeneration of macula correlation).In addition, these compounds can be used as activating agent to resist hyperplasia sexual disorder such as thyroid (such as stroma of ovary blood vessel strengthening, is characterized in that many for hypertrophy (particularly Graves disease (Grave ' s disease)) and cyst Capsule Ovary Syndrome (Stein-Leventhal syndrome) and POLYCYSTIC KIDNEY DISEASE, because these diseases need vascular cell Hypertrophy be used for growing and/or shift).
In other embodiment again, these compounds described here can be used for treating cancer, and for example, B cell is Hypertrophic Disorder, these disorders include but is not limited to diffusivity large B cell lymphoid tumor, follicular lymphoma, chronic lymphocytic lymph Tumor, chronic lymphocytic leukemia, B cell prolymphocytic leukemia, lymph blood plasma lymphoma/Walden Si TelunMacroglobulinemia, splenic marginal zone lymphoma, plasma cell spinal cord tumor, blood plasma cell tumour, tie outward flange Area's B cell lymphoma, tuberosity marginal zone B-cell lymphoma, lymphoma mantle cell, vertical diaphragm (thymus) large B cell lymphoid tumor, blood Large B cell lymphoid tumor in pipe, constitutional hydrops lymphoma, Hugh Burkitt (Burkitt) lymphoma/leukemia, lymphoma sample meat The swollen disease of bud, cancer of pancreas, entity or neoplastic hematologic disorder, optimum or malignant tumor, the brain cancer, renal carcinoma (as renal cell carcinoma (RCC)), squamous is thin Born of the same parents' cancer, salivary-gland carcinoma, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, the moon Road, endometrium, cervix uteri, testis, genitourinary tract, esophaguses, larynx, skin, bone or thyroid sarcoma, glioblastoma, become Neurocytoma, multiple spinal cord tumor or human primary gastrointestinal cancers (especially colon cancer or colorectal adenomas or cervical region and head tumor), Epidermal hyperplasia, psoriasises, prostatic hyperplasia, tumor, neoplasia (the neoplasia of epithelial of epithelial character Character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, nonsmall-cell lung cancer, lymphoma (includes, example As, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also referred to as Huo Qijin (Hodgkin's) or Hodgkin (Hodgkin's disease))), breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, spermocytoma, melanoma, or Leukemia.
In other embodiment again, these compounds described here can be used for treating behcets disease (Behcet's Disease), osteoporosises, osteocarcinoma and Bone tumour, Sjogren's syndrome, contact dermatitis and other eczema-like dermatitis, seborrheica Dermatitis, lichen planuss, epidermolysis bullosa, angioedema, vasculitises, Cutaneous eosinophilia or spring Conjunctivitis.
In other embodiment again, these compounds described here can be used for treating those being characterized as nasal mucosa inflammation Disease, including acute rhinitises, anaphylaxis, atrophic rhinitises, and chronic rhinitiss (include caseous rhinitis, hypertrophic rhinitis, pus Property rhinitis, rhinitis sicca and medicamentous rhinitiss)；Membranous rhinitis (includes croupus, fibroids and pseudomembranous rhinitis and lymph Tuberculous rhinitis), seasonal rhinitises' (include nervous rhinitises (pollinosis) and vasomotor rhinitiies), osteitis tuberculosa cystica, peasant Lung and relevant disease, fiber-like lung and idiopathic interstitial pneumonia.
Have in the present invention chemical formula (I) compound can be used alone or with other reagent (for example, therapeutic agent) It is applied in combination, described other reagent is to be selected for target by technical staff.For example, this other reagent can be Therapeutic agent, this therapeutic agent art-recognized be the disease of the compounds for treating for the treatment present invention or symptom is useful 's.Other reagent can also be to confer to the reagent of therapeutic combination advantageous attributes, for example, affect the reagent of composition viscosity.
Should be further understood that, these combinations will being included in the present invention are useful to its target Compositionss.Following reagent is intended merely to illustrate, and does not play any restriction effect.As a present invention part described group Conjunction can be the present invention compound and at least one selected from following reagent.This combination can also include more than one other medicines Thing, such as two or three other drugs, so long as combination formed compositionss be capable of its predetermined action.
Preferably combination is one or more nonsteroidal anti-inflammatory, also referred to as NSAID, and NSAID is included as ibuprofen Deng medicine.Other preferably combine is corticosteroid, including prednisolone；As the compounds for treating patient with reference to the present invention When, by gradually decreasing required steroid dosage reduction or even eliminating the side effect known to steroid use.Can be with The non-limiting examples that the present invention has the therapeutic agent for rheumatoid arthritiss of compound combination of chemical formula (I) include The following：One or more cell factor inhibiting anti-inflammatory agent (CSAID)；Other Human cytokine or somatomedin anti- Body or antagonist, such as TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-12, IL-15, IL- 16th, IL-21, IL-23, interferon, EMAP-II, GM-CSF, FGF, MMP-13 and PDGF.The compound of the present invention can with thin Cellular surface molecule (such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), the Antibody Combination of CD90, CTLA or their part of inclusion CD154 (gp39 or CD40L).
The preferred combination of therapeutic agent can intervene the different point in autoimmune and subsequent inflammatory cascade；Preferably Example include TNF antagonist as chimeric, humanized or human TNF antibody, D2E7 (United States Patent (USP) 6,090,382, HUMIRATM)、CA2(REMICADETM)、SIMPONITM(goli mumab), CIMZIATM、ACTEMRATM, CDP571 and solvable P55 or p75TNF receptor, its derivant (p75TNFR1gG (ENBRELTM) or p55TNFR1gG (Lenercept) and also There is TNF α invertase (TACE) inhibitor；For the same reason, similarly, IL-1 inhibitor (interleukin-1-converting Enzyme Inhibitor, IL-1RA etc.) can be effective.Other preferably combine including interleukin-11.Other preferably combine again It is the important factor of the others of autoimmune reaction, wherein these combinations are worked, depended on IL- with IL-18 function parallelization 18 functions are worked or are worked with IL-18 function cooperation；Especially preferably IL-12 antagonist, including IL-12 antibody and can Molten IL-12 receptor, or IL-12 associated proteins.Show that but IL-12 and IL-18 has the function of overlap uniqueness, and this The combination of both antagonisies is maximally effective.Another preferably combines again is non-expendable anti-CD4 inhibitor.And other Preferably combination includes the antagonist of stimulation channels CD80 (B7.1) or CD86 (B7.2) altogether, these antagonisies include antibody, can Dissolubility receptor or antagonist part.
The compound in the present invention with chemical formula (I) can also be with following agent combination, such as：Methotrexate, 6- mercapto Base purine, imuran sulfasalazine, mesalazine, olsalazine chloroquine/hydroxychloroquine, penicillamine, golden sulfur Fructus Mali pumilae Acid group (intramuscular and oral), imuran, Colchicine, corticosteroid (oral, sucking and local injection), β- 23 adrenergic receptor agonists (albuterol, terbutaline, salmaterol), xanthine (theophylline, aminophylline), color are sweet Sour sodium, nedocromil, ketotifen, isopropyl support amine and oxitropium bromide, cyclosporin, FK506, pareira mycin, mycophenolate, carry out fluorine Meter Te, NSAID (for example, ibuprofen), corticosteroid (for example, prednisolone), phosphodiesterase inhibitor, adenosine are exciting Agent, antithrombotic agent, complement inhibitor, epinephrine agent, (such as TNF α or IL-1 are (for example, by pro-inflammatory cytokine NIK, IKK, JAK1, JAK2, JAK3, p38 or map kinase inhibitor)) intrusion signal transduction reagent, IL-1 β conversion enzyme level Agent, T- Signaling Inhibitors On Specific (such as kinase inhibitor), inhibitors of metalloproteinase, willow nitrogen sulphur arsenic pyridine, 6- sulfydryl are fast Purine, angiotensin converting enzyme inhibitor, solvable cytokine receptor and its derivant (for example solvable p55 or p75TNF Receptor and derivant p75TNFRIgG (EnbrelTM) and p55TNFRIgG (Lenercept), sIL-1RI, IL-1RII, sIL- 6R), anti-inflammatory cytokines (such as IL-4, IL-10, IL-11, IL-13 and TGF β), Celecoxib, Folic Acid, sulphuric acid hydroxylation chlorine Quinoline, rofecoxib, Embrel, Infliximab, naproxen, valdecoxib, willow nitrogen sulphur arsenic pyridine, methylprednisolone, U.S. Lip river former times Health, methylprednisolone acetate, acid gold sodium, aspirin, Triamcinolone Acetonide, propoxyphene napsylate/acetaminophen, leaf Acid, nabumetone, diclofenac sodium, pyrroles Xikang, Etodolac, diclofenac sodium, oxaprozin, oxycodone HCl, tartaric acid Hydrocodone/acetaminophen, Diclofenac Sodium/Misoprosrol, fentanyl, Ah that's Radix Angelicae Dahuricae element (anakinra), tramadol HCl, salsalate, Su Lin acid, cobalamin/fa/ pyridoxol, acetaminophen, Alendronate sodium, prednisolone, sulphuric acid Coffee, lidocaine hydrochloride, indomethacin, glucosamine sulf/ chrondroitin, amitriptyline HCl, sulfadiazine, oxycodone HCl/ acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole, cyclophosphamide, Rituximab, Tropsch imatinib, IL-1TRAP, MRA, CTLA4-IG, IL-18BP, anti-IL-12, anti-IL15, BIRB-796, SCIO-469, VX- 702nd, AMG-548, VX-740, roflumilast, IC-485, CDC-801, S1P1 agonist (such as FTY720), the suppression of PKC family Agent (such as Lu Baisita or AEB-071) and U.S. rope do not reach name.Preferably combination includes methotrexate or leflunomide, and In the case of moderate or severe rheumatoid arthritis, as mentioned above, including cyclosporin and anti-TNF antibody.
The therapeutic agent for inflammatory bowel that the compound that can have chemical formula (I) with the present invention combines non-limiting Example includes the following：Budesonide；Epidermal growth factor；Corticosteroid；Cyclosporin, willow nitrogen sulphur arsenic pyridine；Amino water Poplar hydrochlorate；Ismipur；Imuran；Metronidazole；Lipoxygenase inhibitor；Mesalazine；Olsalazine；Balsalazide； Antioxidant；Thromboxane inhibitor；IL-1 receptor antagonist；Anti- IL-1 β monoclonal antibody；Anti- IL-6 monoclonal antibody；Raw The long factor；Elastase inhibitor；Pyridine radicals-imidazolium compoundss；Other Human cytokine or growth factor antibodies or short of money Anti-agent, such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM- CSF, FGF and PDGF；Cell surface molecule, such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their part；Methotrexate；Cyclosporin；FK506；Pareira mycin；Mycophenolate；Leflunomide； NSAID, such as ibuprofen；Corticosteroid, such as prednisolone；Phosphodiesterase inhibitor；Adenosine agonistses；Antithrombotic shape Become agent；Complement inhibitor；Epinephrine agent；By pro-inflammatory cytokine (such as TNF α or IL-1 (for example, NIK, IKK, p38 Or map kinase inhibitor)) intrusion signal transduction reagent；IL-1 β converting enzyme inhibitor；TNF α converting enzyme inhibitor；T- cell Signal transduction inhibitor, such as kinase inhibitor；Inhibitors of metalloproteinase；Willow nitrogen sulphur arsenic pyridine；Imuran；6- sulfydryl is fast Purine；Angiotensin converting enzyme inhibitor；Solvable cytokine receptor and its derivant (for example solvable p55 or p75TNF Receptor, sIL-1RI, sIL-1RII, sIL-6R) and anti-inflammatory cytokines (such as IL-4, IL-10, IL-11, IL-13 and TGF β).The preferred embodiment of the therapeutic agent for Crohn disease that can combine with the compound with chemical formula (I) includes following ?：TNF antagonist (such as anti-TNF antibody), D2E7 (United States Patent (USP) 6,090,382, HUMIRATM)、CA2(REMICADETM)、 CDP571, TNFR-Ig construct, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM) inhibitor and PDE4 inhibitor.The compound with chemical formula (I) can be combined with the following：Corticosteroid, such as budesonide and Dexamethasone；Willow nitrogen sulphur arsenic pyridine, 5- aminosalicylic acid；Olsalazine；Examination with interference pro-inflammatory cytokine synthesis or effect Agent, such as IL-1, such as IL-1 β converting enzyme inhibitor and IL-1ra；T cell signal transduction inhibitor, such as tyrosine kinase Inhibitor；Ismipur；IL-11；Mesalazine；Prednisone；Imuran；Purinethol；Infliximab；Methyl sprinkles Buddhist nun Loose sodium succinate；Diphenoxylate/atropine sulfate；Loperamide Hydrochloride；Methotrexate；Omeprazole；Folic Acid；Ciprofloxacin/ Dextrose-water；Hydrocodone tartrate/acetaminophen；Quadracycline；Fluocinonide；Metronidazole；Thimerosal/boric acid； Colestyramine/sucrose；Ciprofloxacin hydrochloride；Hyoscyamine sulfate；Isonipecaine hydrochloride；Midazolam hydrochloride；Oxycodone HCl/ acetaminophen；Promethazine hydrochloride；Sodium phosphate；Sulfamethoxazole/trimethoprim；Celecoxib；Polycarbophil；Naphthalene Sulfonic acid propoxyhene；Hydrocortisone；Multivitamin；Balsalazide disodium；Codeine phosphate/acetaminophen；Colesevelam HCl；Cobalamin；Folic Acid；Left fluorine oxygen sand star；Methylprednisolone；Natalizumab and interferon-γ.
The non-limiting reality of the therapeutic agent for multiple sclerosis that can combine with the compound with chemical formula (I) Example includes the following：Corticosteroid；Prednisolone；Methylprednisolone；Imuran；Cyclophosphamide；Cyclosporin； Methotrexate；4-aminopyridine；Tizanidine；Interferon-beta 1a (A WonasiBayer gene (Biogen))；Interferon-beta 1b (BetaferonVery grand (Chiron)/primary Simon Rex (Berlex))； Alferon N) (interferon science (Sciences)/liana (Fujimoto)), interferon-' alpha ' (Alpha Wei Shiman (AlfaWassermann)/J＆J), interferon beta 1A-IF (Xue Lannuo (Serono)/anapnotherapy (InhaleTherapeutics)), Peg interferon alpha 2 b (by comprehensive (the Enzon)/Schering Plough of grace (Schering-Plough)), Copolymer 1 (Cop-1；Cop1Ti Wa pharmaceutical industries company (Teva Pharmaceutical Industries,Inc.)；Hyperbaric oxygen；Intravenous immunoglobuin；Cladribine；Other Human cytokine or somatomedin Antibody or antagonist and their receptor, such as TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II, GM-CSF, FGF and PDGF.The compound with chemical formula (I) can be with cell surface molecule (such as CD2, CD3, CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or Their part) antibody combined.The compound with chemical formula (I) can also be with the following agent combination：Such as ammonia Methopterin, cyclosporin, FK506, pareira mycin, mycophenolate, leflunomide, S1P1 agonist, NSAID (such as cloth Lip river Fragrant), corticosteroid (such as prednisolone), phosphodiesterase inhibitor, adenosine agonistses, antithrombotic agent, complement suppression Preparation, epinephrine agent, by pro-inflammatory cytokine (such as TNF α or IL-1 (for example, NIK, IKK, p38 or map kinase suppression Preparation)) intrusion signal transduction reagent, IL-1 β converting enzyme inhibitor, tace inhibitor, T- Signaling Inhibitors On Specific example As kinase inhibitor, inhibitors of metalloproteinase, willow nitrogen sulphur arsenic pyridine, imuran, Ismipur, angiotensin conversion Enzyme inhibitor, solvable cytokine receptor and its derivant (for example solvable p55 or p75TNF receptor, sIL-1RI, sIL- 1RII, sIL-6R) and anti-inflammatory cytokines (such as IL-4, IL-10, IL-13 and TGF β).
The preferred example of the therapeutic agent for multiple sclerosis that can combine with the compound with chemical formula (I) Including the following：Interferon-beta, such as IFN β 1a and IFN β 1b；Cop1, corticosteroid, cysteine proteinase suppression Agent (such as cysteine proteinase -1 inhibitor), the antibody of IL-1 inhibitor, tnf inhibitor and CD40L and CD80.
The compound with chemical formula (I) can also be with the following agent combination, such as：Alemtuzumab, dronabinol, Zenapax, mitoxantrone, xaliproden hydrochlorate, Fampridine, copaxone acetate, natalizumab, sinnabidol, α- Immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptor anagonists, BBR-2778, OK a karaoke club Gu Alin (calagualine), CPI-1189, LEM (mitoxantrone liposome), THC.CBD (cannabinoid agonists), MBP-8298, U.S. Rope does not reach name (PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, anger Ruo Wakasi vaccine (neurovax), the non-Buddhist nun of pyrrole Ketone allotrope 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-β 2, for Ta Motai, VLA-4 short of money Anti-agent (such as TR-14035, VLA4Ultrahaler, Antegran-ELAN/ Bayer gene (Biogen)), interferon gamma antagonism Agent and IL-4 agonist.
The non-limiting reality of the therapeutic agent for ankylosing spondylitises that can combine with the compound with chemical formula (I) Example includes the following：Ibuprofen, diclofenac sodium, misoprostol, naproxen, Meloxicam, indomethacin, diclofenac Sodium, Celecoxib, rofecoxib, willow nitrogen sulphur arsenic pyridine, methotrexate, imuran, minocycline hydrochloride, prednisone and anti- TNF antibody, D2E7 (United States Patent (USP) 6,090,382；HUMIRATM)、CA2(REMICADETM), CDP571, TNFR-Ig construct, (p75TNFRIgG(ENBRELTM) and p55TNFRIgG (LENERCEPTTM).
The non-limiting examples of the therapeutic agent for asthma that can combine with the compound with chemical formula (I) include with Lower items：Albuterol, salmaterol/fluticasone, Menglusitena, fluticasone propionate, budesonide, prednisone, Salmaterol xinafoate, Levalbuterol HCl, salbutamol sulfate/isopropyl support amine, Inflamase, Qu An Nai De, beclomethasone dipropionate, isopropyl support amine bromide, Azithromycin, skin butanol acetate, prednisolone, theophylline anhydrous, Methyllprednisolone sodium succinate, clarithromycin, zafirlukast, Formoterol Fumarate, influenza virus vaccine, amoxicillin three Water acid, flunisolide, allergy injection, sodium cromoglicate, fexofenadine hydrochloride, flunisolide/menthol, A Moxi Woods/clavulanic acid, left fluorine oxygen sand star, inhaler auxiliary device, guaifenesin, DEXAMETHASONE SODIUM PHOSPHATE, Moxifloxacin HCl, Doxycycline hydrochloride, guaifenesin/dextromethorphan, p- ephedrine/cod/ chlorphenamine, Gatifloxacin, cetirizine hydrochloric acid Salt, momestasone furoate, salmaterol xinafoate, benzonatate, cephalo element benzyl, pe/ hydrocodone/chlorphenamine, cetirizine HCl/ pseudoephedrine, phyenlephrinium/cod/ promethazine, codeine/promethazine, cefprozil, dexamethasone, more wound glycerol Ether/Pseudoephedrine, chlorphenamine amine/hydrocodone, sodium nedocromil, terbutaline sulfate, epinephrine, Methyllprednisolone Imperial, anti-IL-13 antibody and orciprenaline sulfate.
The non-limiting examples of the therapeutic agent for COPD that can combine with the compound with chemical formula (I) include with Lower items：Salbutamol sulfate/isopropyl support amine, isopropyl support amine bromide, salmaterol/fluticasone, albuterol, Sha Mei Special sieve xinafoate, fluticasone propionate, prednisone, theophylline anhydrous, Methyllprednisolone sodium succinate, Menglusitena, Budesonide, Formoterol Fumarate, Triamcinolone Acetonide, left fluorine oxygen sand star, guaifenesin, Azithromycin, beclometasone dipropyl Hydrochlorate, Levalbuterol HCl, flunisolide, ceftriaxone sodium, AMOX, Gatifloxacin, zafirlukast, Ah Amdinocillin/clavulanic acid, flunisolide/menthol, chlorphenamine amine/hydrocodone, orciprenaline sulfate, Methyllprednisolone Dragon, momestasone furoate, p- ephedrine/cod/ chlorphenamine, skin butanol acetate, p- ephedrine/Loratadine, terbutaline sulfur Hydrochlorate, TB, (R, R)-formoterol, TgAAT, cilomilast and roflumilast.
The non-limiting examples of the therapeutic agent for HCV that can combine with the compound with chemical formula (I) include with Lower items：Interferon-' alpha ' -2 α, interferon-' alpha ' -2 β, interferon-' alpha ' con1, interferon-' alpha '-n1, glycol interferon-α -2 α, glycol interferon-α -2 β, virazole, Peg-IFN alpha-2b -2b virazole, ursodesoxycholic acid, glycyrrhizic acid, thymus Method is new, Maxamine, VX-497 and treat any reagent of HCV by disturbing the following：HCV polymerase, HCV albumen Enzyme, HCV unwindase and HCV IRES internal ribosome entry site.
Can combine with the compound with chemical formula (I) for specificity lung fiber disease therapeutic agent non-limiting Example includes the following：Prednisone, imuran, albuterol, Colchicine, salbutamol sulfate, digoxin, γ Interferon, Methyllprednisolone sodium succinate, lorazepam, furosemide, lisinopril, nitroglycerin, aldactone, ring Phosphamide, isopropyl support amine bromide, D actinomycin D d, alteplase, fluticasone propionate, left fluorine oxygen sand star, orciprenaline sulfur Hydrochlorate, morphine sulfate, oxycodone HCl, potassium chloride, Triamcinolone Acetonide, anhydrous tacrolimuss, calcium, interferon-' alpha ', methotrexate, mould Phenols acids and interferon-γ -1 β.
The non-limiting examples bag of the therapeutic agent for myocardial infarction that can combine with the compound with chemical formula (I) Include the following：Aspirin, nitroglycerin, spectinomycin hydrochloride, Enoxaparin Sodium, heparin sodium, clopidogrel two sulphuric acid Salt, carvedilol, Atenolol, morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril, the different Pyrusussuriensiss of single nitric acid Ester, digoxin, furosemide, simvastatin, ramipril, tenecteplase, uh that Puli, torasemide, reteplase, losartan Potassium, quinapril hydrochloride/magnesium carbonate, bumetanide, alteplase, enalaprilat, amiodarone hydrochloride, tirofiban HCl m- hydrate, diltiazem hydrochloride, Captopril, irbesartan, Valsartan, propranolol hydrochloride, fosinopril Sodium, lidocaine hydrochloride, eptifibatide, Cefazolin sodium, atropine sulfate, aminocaproic acid, aldactone, interference Element, sotalol hydrochlorate, potassium chloride, docusate sodium, dobutamine HCl, alprazolam, pravastatin sodium, atropic cut down him Spit of fland calcium, midazolam hydrochloride, isonipecaine hydrochloride, sorbide nitrate, epinephrine, dopamine hydrochloride, bivalirudin, Rosuvastatin, according to pool for quilt/simvastatin, avasimibe and Ka Libo.
The non-limiting examples for psoriatic therapeutic agent that can be combined with the compound with chemical formula (I) are included The following：Its salts, clobetasol propionate, Triamcinolone Acetonide, ulobetasol propionate, tazarotene, methotrexate, vinegar Sour fluocinolone acetonide, the enhancing of betamethasone normal heptane, Fluocinonide, A Quting, tar shampoo, celestone-V, furancarboxylic acid Mometasone, Ketoconazole, pramocaine/fluocinolone acetonide, hydrocortisone, flurandrenolide, carbamide, betamethasone, clobetasol propanoic acid Salt/emollient, fluticasone propionate, Azithromycin, hydrocortisone, moisturizing formula, Folic Acid, desonide, pimecrolimus, coal Tar, diflorasone diacetin, Embrel Folic Acid, lactic acid, methoxsalen, hc/ bismuth pair gallium/zinc oxide/resorcin, first Base prednisolone acetate, prednisone, sunscreen, halcinonidedcorten, salicylic acid, dithranol, clocortolone, distilled tar fraction, coal tar The acid of oil/water poplar, coal tar/salicylic acid/sulfur, desoximetasone, stable, emollient, Fluocinonide/emollient, mineral oil/castor Oleum Sesami/that newborn spore element, mineral oil/Oleum Arachidis hypogaeae semen, oil/isopropyl myristate, psoralen, salicylic acid, soap/tribromo are husky Logical sequence, thimerosal/boric acid, Celecoxib, Infliximab, cyclosporin, Ah method's Saite, efalizumab, tacrolimuss, U.S.A are not Department, PUVA, UVB, willow nitrogen sulphur arsenic pyridine, ABT-874 and this special Kona monoclonal antibody (ustekinamab) of plumage.
The therapeutic agent for psoriasis arthropathica that can combine with the compound with chemical formula (I) non-limiting Example includes the following：Methotrexate, Embrel, rofecoxib, Celecoxib, Folic Acid, willow nitrogen sulphur arsenic pyridine, naproxen, Leflunomide, methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate, prednisone, Su Lin acid, betamethasone are just Heptane enhancing, Infliximab, methotrexate, Folic Acid, Triamcinolone Acetonide, diclofenac sodium, dimethyl sulfoxide, pyrroles Xikang, double chlorine Fragrant acid sodium, cheese Lip river phenol, Meloxicam, methylprednisolone, nabumetone, tolmetin, its salts, ring spore bacterium Element, Diclofenac Sodium/Misoprosrol, Fluocinonide, glucosamine sulphate, acid gold sodium, hydrocodone tartrate/to second Acylamino- phenol, ibuprofen, risedronate sodium, sulfadiazine, thioguanine, valdecoxib, Ah method's Saite, D2E7 (United States Patent (USP) 6,090,382, HUMIRATM) and efalizumab.
The non-limiting examples of the therapeutic agent for restenosiss that can be combined with the compound with chemical formula (I) are included The following：Pareira mycin, paclitaxel, everolimuses, tacrolimuss, ABT-578 and acetaminophen.
The non-limiting examples of the therapeutic agent for sciatica that can combine with the compound with chemical formula (I) Including the following：Hydrocodone tartrate/acetaminophen, rofecoxib, cyclobenzaprine HCl, methylprednisolone, Nabumetone Life, ibuprofen, oxycodone HCl/ acetaminophen, Celecoxib, valdecoxib, methylprednisolone acetate, prednisone, Codeine phosphate/acetaminophen, tramadol HCl/ acetaminophen, metaxalone, Meloxicam, methocarbamol, salt Lidocaine hydrochloride, diclofenac sodium, Jia Bafending, dexamethasone, carisoprodol, Ketorolac Tromethamine, indomethacin, to second Acylamino- phenol, stable, nabumetone, oxycodone HCl, tizanidine HCl, Diclofenac Sodium/Misoprosrol, propoxyphene n- Pap, asa/ hydroxyl examines/oxycodone ter, ibuprofen/hydrocodone bit, tramadol HCl, Etodolac, propoxyphene HCl, amitriptyline HCl, carisoprodol/codeine phosphate/asa, morphine sulfate, multivitamin, naproxen sodium, orphenadrine citrate and hydroxyl Base is stabilized.
The preferred example bag of the therapeutic agent for SLE (lupus) that can combine with the compound with chemical formula (I) Include the following：NSAID, such as diclofenac sodium, naproxen, ibuprofen, pyrroles Xikang, indomethacin；COX2 inhibitor, example As Celecoxib, rofecoxib, valdecoxib；Anti- anti-malarial drug, such as hydroxychloroquine；Steroid, such as prednisone, bold and vigorous Buddhist nun Song Long, budesonide, dexamethasone；Cytotoxin, such as imuran, cyclophosphamide, mycophenolate, methotrexate； PDE4 inhibitor or purine synthetic inhibitor, for exampleHave chemical formula (I) compound can also with following Item agent combination, for example：Willow nitrogen sulphur arsenic pyridine, 5- aminosalicylic acid, olsalazine,With intervention pro-inflammatory cytokine The synthesis of (such as IL-1, such as cystatin such as IL-1 β converting enzyme inhibitor and IL-1ra), generation or work Reagent.The compound with chemical formula (I) can also be used together with T cell signal transduction inhibitor, such as tyrosine Kinase inhibitor；Or the molecule of targeting T-cells anakmetomeres, such as CTLA-4-IgG or anti-B7 family antibody, anti-PD-1 family Race's antibody.The compound with chemical formula (I) can be with IL-11 or anti-cytokine Antibody Combination, such as Buddhist promise trastuzumab (fonotolizumab) (anti-IFNg antibody), or anti-receptor receptor antibody, for example anti-IL-6 receptor antibody and B- cell table Face molecular antibody.Have chemical formula (I) compound can also with LJP394 (Abbe not this) (consume or passivation B- cell examination Agent) it is used together, such as Rituximab (anti-CD 20 antibodies), Baily monoclonal antibody-B (anti-BlyS antibody), TNF antagonist (example As anti-TNF antibody), D2E7 (United States Patent (USP) 6,090,382；HUMIRATM)、CA2(REMICADETM)、CDP571、TNFR-Ig Construct, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG (LENERCEPTTM).
In the present invention, defined below is applicatory:
" therapeutically effective amount " is that have the compound of chemical formula (I) or the combination of two or more such compounds Amount, this amount suppresses the progress of disease wholly or in part or at least partly improves one or more symptom of this disease.Treatment is effectively Amount can also be that prevention is upper effectively to be measured.This amount will depend upon the body size of patient and sex, has disease to be treated, disease The order of severity and sought result.For given patient, therapeutically effective amount can be passed through known to those skilled in the art Method be determined.
" pharmaceutically acceptable salt " refers to those and keeps the biological effectiveness of free alkali and the salt of characteristic and lead to Cross and mineral acid (such as hydrochloric acid, hydrobromic acid, sulfacid, nitric acid and phosphoric acid) or organic acid (such as sulfonic acid, carboxylic acid, organophosphors Acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, breast Acid, tartaric acid (such as (+) or (-)-tartaric acid or its mixture), aminoacid (such as (+) or (-)-aminoacid or its mixing Thing) and analog) reaction obtain those salt.These salt can be prepared from known compounds by those skilled in the known methods.
Have acidic substituent some compounds with chemical formula (I) can as with pharmaceutically acceptable alkali Salt exists.The present invention includes these salt.The example of these salt includes sodium salt, potassium salt, lysinate and arginine salt.Can pass through Method known to those skilled in the art prepares these salt.
Some compounds with chemical formula (I) and their salt can presented in exceeding a kind of crystal and this Bright comprise every kind of crystal form and its mixture.
Some compounds with chemical formula (I) and their salt can be presented in solvates, such as hydrate, And the present invention comprises every kind of solvate and its mixture.
Some compounds with chemical formula (I) can comprise one or more chiral centres, and is lived with different optics Presented in property.When the compound with chemical formula (I) comprises a chiral centre, this compound is with two kinds of enantiomeric forms Exist and the present invention comprises both enantiomer and its mixture, such as racemic mixture.Using in the art common Method known to the skilled person can split enantiomer, and (these salt can be such as example to pass through the diastereoisomeric salt of formation Separated by crystallization)；By the diastereoisomeric derivant of formation or complex, (these derivants or complex can examples As separated by crystallization, gas liqud chromatography or liquid chromatograph)；Reagent special with a kind of enantiomer for a kind of enantiomer is entered The selective reaction of row (for example, enzymatic esterification effect)；Or in a chiral environment gas liqud chromatography or liquid chromatograph (example As on for example there is a kind of chiral support of the silicon dioxide of the chiral ligand of combination or in a kind of presence of chiral solvent Under).It should be appreciated that wherein desired enantiomer passes through one of lock out operation as described above is converted into another kindization Learn entity it is desirable to further step is discharging desired enantiomeric form.Alternately, specific enantiomer can lead to Cross using multiple optically-active reagent, asymmetric synthesis of substrate, catalyst or solvent or by being transformed into separately a kind of enantiomer A kind of (by asymmetric conversion) is being synthesized.
When the compound with chemical formula (I) comprises more than a chiral centre, this compound can be with diastereoisomeric Form exists.These diastereoisomeric compounds, such as chromatograph can be separated by method known to those skilled in the art Method or crystallization process and single enantiomer can carry out separating as described above.The present invention includes the change with chemical formula (I) Each diastereomer of compound and its mixture.
Some compounds with chemical formula (I) can be using presented in different tautomerisms or as different geometry Isomer exists, and the present invention includes each tautomer of compound and/or the geometric isomer with chemical formula (I) And its mixture.
Some compounds with chemical formula (I) can with different can be that separable stable conformational forms exist. Because the torsion of the limited rotation around the single key of asymmetry is asymmetric, such as because steric hindrance or ring strain, Ke Yiyun Permitted the separation of different conformers.The present invention include each conformer of compound with chemical formula (I) and its Mixture.
Some compounds with chemical formula (I) can be presented in amphion and the present invention is included with chemistry Each zwitterionic form of the compound of formula (I) and its mixture.
Term " prodrug " as used herein refers to be converted to active compound in vivo by some physiochemistry processes Reagent (for example, the prodrug of physiology pH is converted to the medicament forms wanted).Prodrug be often useful because in some feelings Under condition, they are easier to give than active compound.For example, they can be by being orally administered to and bioavailable, and this mother Body medicine is not all right.This prodrug also has the dissolubility of improvement in pharmaceutical composition compared to active compound.One reality of prodrug Example (not limit) will be a kind of compound of the present invention, wherein this compound be as ester (should " prodrug ") given with Promote the transmission (wherein water solublity is harmful) of cross-cell membrane, but once be in that in this cell, (wherein water-soluble is that have Benefit) it then being metabolized property be hydrolyzed into carboxylic acid.
Prodrug has much useful characteristic.For example prodrug can have more water solublity than final medicine, thus promoting to be somebody's turn to do The intravenous administration of medicine.Prodrug can also have higher levels of oral administration biaavailability than final medicine.After giving, should Prodrug by enzymatic lysises or by chemical cracking to deliver final medicine in blood or tissue.
Exemplary prodrug discharges corresponding free acid, and this kind of hydrolyzable of these compounds of the present invention in cracking Formation ester residue include but is not limited to carboxylic acid substituent, wherein this free hydrogen is substituted by the following：(C1-C4) alkyl, (C1-C12) alkanoyloxymethyl, (C4-C9) 1- (alkanoyloxy) ethyl, there is 1- methyl isophthalic acid-(alkane from 5 to 10 carbon atoms Acyloxy)-ethyl, there is alkoxyl alkanoyloxymethyl from 3 to 6 carbon atoms, there is 1- (alkane from 4 to 7 carbon atoms Epoxide carbonyloxy group) ethyl, there is 1- methyl isophthalic acid-(alkoxyl carbonyloxy group) ethyl from 5 to 8 carbon atoms, have from 3 to 9 N- (alkoxy carbonyl) amino methyl of carbon atom, there is 1- (N- (alkoxy carbonyl) amino) second from 4 to 10 carbon atoms Base, 3- phthalidyl, 4- furanonyl, gamma-butyrolacton -4- base, double-N, N- (C1-C2) alkyl amino (C2-C3) alkyl (such as β-two Methylaminoethyl), carbamoyl-(C1-C2) alkyl, N, N- bis- (C1-C2)-alkyl-carbamoyl-(C1-C2) alkyl and Piperidines-, pyrrolidinyl-or morpholino (C2-C3) alkyl.
The release of other Exemplary prodrug has the alcohol of chemical formula (I), and wherein the free hydrogen of hydroxyl substituent is (as R1Comprise hydroxyl Base) substituted by the following：(C1-C6) alkanoyl epoxide methyl, 1- ((C1-C6) alkanoyl epoxide) ethyl, 1- methyl isophthalic acid- ((C1-C6) alkanoyl epoxide) ethyl, (C1-C12) alkoxyl carbonyl oxy-methyl, N- (C1-C6) alkoxycarbonyl amino-methyl, Succinum one acyl group, (C1-C6) alkanoyl, alpha-amido (C1-C4) alkanoyl, aryl-acyl and alpha-amido acyl group or alpha-amido acyl Base-alpha-amido acyl group, wherein said alpha-amido acyl moiety is independently to be found in protein, P (O) (OH)2、-P(O)(O(C1- C6) alkyl)2Or the natural L-amino acids in glycosyl (this group results from the disengaging of the hydroxyl of the hemiacetal of carbohydrate) Any part.
This term " heterocycle " as used herein, " heterocyclic radical " or " sub- heterocyclic radical " include non-aromatic ring system (bag Include but be not limited to monocyclic, bicyclo-, three rings and volution), this non-aromatic ring system can be fully saturated or comprise one or Multiple unsaturation units, for exempting to become suspicious, this undersaturated degree does not produce aromatic ring system；And it is former to have 5 to 12 carbon Sub (including at least one hetero atom, such as nitrogen, oxygen or sulfur).(should not be construed as limiting the invention for exemplary purposes Scope), below for the example of heterocycle：Azepine base, azetidinyl, indolinyl, iso-dihydro-indole-group, morpholinyl, piperazine Piperazine base, piperidyl, pyrrolidinyl, quininuclidinyl, thio-morpholinyl, THP trtrahydropyranyl, tetrahydrofuran base, tetrahydro indole base, sulfur For morpholinyl and tropane base.
This term " heteroaryl " as used herein or " inferior heteroaryl " include aromatic ring system, including but not limited to, Monocyclic, bicyclo- and three rings；And there are 5 to 12 carbon atoms (including at least one hetero atom, such as nitrogen, oxygen or sulfur).For Exemplary purpose (should not be construed as limiting the invention scope)：Azaindole base, benzo (b) thienyl, benzimidazolyl, benzene And furyl, benzoxazolyl group, benzothiazolyl, diazosulfide base, benzodiazole base, furyl, imidazole radicals, imidazo Pyridine radicals, indyl, indazolyl, isoxazolyl, isothiazolyl, di azoly, oxazolyl, purine radicals, pyranose, pyrazinyl, Pyrazolyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, pyrrolo- [2,3-d] pyrimidine radicals, pyrazoles [3,4-d] pyrimidine radicals, quinolyl, quinoline azoles Quinoline base, triazolyl, thiazolyl, thio-phenyl, tetrazole radical, thiadiazolyl group, thienyl, 6H- pyrrolo- [2,3-e] [1,2,4] three Azoles [4,3-a] pyrazinyl, 6H- imidazo [1,5-a] pyrrolo- [2,3-e] pyrazinyl, 1,6- pyrazoline [3,4-d] pyrrolo- [2,3-b] pyridine, 3H-3,4,6,8a- tetra- azatropylidenes-octadiene, 3H- imidazo [1,2-a] pyrrolo- [2,3-e] pyrazinyl, Pyrazoles [3,4-d] pyrrolo- [2,3-b] pyridine radicals, the 1,6- dihydro -1,2,5,6- tetrazane-octyl- diene, 3H-3,4,8a- tri- nitrogen Miscellaneous Zhuo-octyl- diene, 6H-3- oxa- -2,5,6- three azatropylidenes-octyl- diene, 3,6- dihydro -2,3,6- four azatropylidenes-octyl- two Alkene, 1,6- dihydro-two pyrrolo- [2,3-b；2 ' 3 '-d] pyridine radicals, 6H-3- thiophene -2,5,6- three azatropylidenes-octyl- diene, 4,5- Dihydro -1H- benzo [b] azatropylidene -2 (3H) -one, 3,4- dihydroquinoline -2 (1H) -one, 2H- benzo [b] [1,4] piperazine -3 (4H) -one or 6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine base or 1,6- glyoxalidine simultaneously [4,5-d] pyrrolo- [2, 3-b] pyridine.
As used herein, " alkyl ", " alkylidene " or symbol such as " (C1-C8) " include the completely full of straight or branched The hydrocarbon of sum.The example of alkyl is methyl, ethyl, propyl group, isopropyl, butyl, amyl group, hexyl and its isomer.As used herein , " thiazolinyl ", " alkenylene ", " alkynylene " and " alkynyl " means C2-C8And the hydrocarbon including straight or branched, these hydrocarbon comprise One or more unsaturation units, one or more double bond for thiazolinyl and one or more three keys for alkynyl.
As used herein, " aromatic series " group (or " aryl " or " arlydene " group) includes aromatic series carbon loop systems (as phenyl) and the Ppolynuclear aromatic loop systems (as naphthyl, xenyl and 1,2,3,4- tetralyl) condensing.
As used herein, " cycloalkyl " or " cycloalkylidene " means C3-C12Monocyclic or multi-ring (for example, bicyclo-, three rings, Volution etc.) fully saturated hydrocarbon.The example of group of naphthene base be cyclopropyl, cyclobutyl, cyclopenta, bicyclo- [1.1.1] amyl group, And cyclohexyl.
As used herein, " cycloalkenyl group " means C3-C12Monocyclic or multi-ring (for example, bicyclo-, three rings, volution etc.) hydrocarbon, should Hydrocarbon has one or more unsaturated bonds but is not equal to aromatic group.The example of cycloalkenyl groups is cyclopentenyl and cyclohexene Base.
As used herein, mass part or substituent group are referred to as " substituted " or " optionally substituted ".When a portion Divide by the modification of one of these terms, unless otherwise noted, it represents known to persons of ordinary skill in the art and can be used for taking Any part of this part in generation can be substituted, and this part includes one or more substituent groups, wherein when more than one During substituent group, then each substituent group is selected independently.The mode that these are used for replacing is well known in the art and/or this Disclose teaching.(should not be construed as limiting the invention scope) for exemplary purposes, be the example of the group of substituent group It is：(C1-C8) alkyl group, (C2-C8) alkenyl group, (C2-C8) alkynyl group, (C3-C10) group of naphthene base, halogen (F, Cl, Br or I), halogenation (C1-C8) alkyl group (such as but not limited to-CF3)、-O-(C1-C8) alkyl group ,=O ,=CH2、-OH、- CH2OH、-CH2NH2、(C1-C4) alkyl-OH ,-CH2CH2OCH2CH3、-S-(C1-C8) alkyl group ,-SH ,-NH (C1-C8) alkyl Group ,-N ((C1-C8) alkyl)2Group ,-NH2、-C(O)NH2、-CH2NHC(O)(C1-C4) alkyl ,-CH2NHC(O)CH2Cl、- CH2NHC(O)CH2CN、-CH2NHC(O)CH2CH2N(CH3)2、-CH2NHC (O) C (=CH2)CH3、-CH2NHC(O)(C2-C4) alkynes Base ,-CH2NHC(O)CH2CH2- piperidyl ,-(C1-C4) alkyl-morpholinyl ,-CH2NHC(O)CH2O- phenyl (wherein appoint by this phenyl Selection of land is replaced by the following：Halogen, (C1-C4) alkoxyl ,-C (O) (C1-C4) alkyl ,-C (O) (C1-C4) alkoxyl ,-C (O) N(H)2、-C(O)N(CH3)2、-C(O)(C1-C6) heteroaryl ,-N (CH3)2、-NHC(O)(C1-C4) alkyl ,-NHC (O) (C2-C4) Thiazolinyl ,-NHC (O) CH2CN、-S(O)2(C1-C4) alkyl ,-S (O)2(C1-C6) heteroaryl ,-S (O)2(C1-C6)(C1-C6) heterocycle Base, 4- methyl piperazine carbonyl ,-(C1-C4) alkyl C (O) NH2、-C(O)NH(C1-C8) alkyl group ,-C (O) N ((C1-C8) alkane Base)2、-C(O)N(H)(C3-C8) group of naphthene base ,-C (O) (C1-C4) alkoxyl ,-NHC (O) H ,-NHC (O) (C1-C8) alkyl Group ,-NHC (O) (C3-C8) group of naphthene base ,-N ((C1-C8) alkyl) C (O) H ,-N ((C1-C8) alkyl) C (O) (C1-C8) alkane Base group ,-NHC (O) NH2、-NHC(O)NH(C1-C8) alkyl group ,-N ((C1-C8) alkyl) C (O) NH2Group ,-NHC (O) N ((C1-C8) alkyl)2Group ,-N ((C1-C8) alkyl) C (O) N ((C1-C8) alkyl)2Group ,-N ((C1-C8) alkyl) C (O) NH ((C1-C8) alkyl) ,-NHCH2- heteroaryl, benzyl ,-OCH2- heteroaryl ,-C (O) H ,-C (O) (C1-C8) alkyl group ,-CN ,- NO2、-S(O)(C1-C8) alkyl group ,-S (O)2(C1-C8) alkyl group ,-S (O)2N((C1-C8) alkyl)2Group ,-S (O)2NH (C1-C8) alkyl group ,-S (O)2NH(C3-C8) group of naphthene base ,-S (O)2NH2Group ,-NHS (O)2(C1-C8) alkyl base Group ,-N ((C1-C8) alkyl) S (O)2(C1-C8) alkyl group ,-(C1-C8) alkyl-O- (C1-C8) alkyl group ,-O- (C1-C8) Alkyl-O- (C1-C8) alkyl group ,-C (O) OH ,-C (O) O (C1-C8) alkyl group, NHOH, NHO (C1-C8) alkyl group s ,- O- halogenation (C1-C8) alkyl group (such as but not limited to-OCF3)、-S(O)2- halogenation (C1-C8) alkyl group (for example but do not limit In-S (O)2CF3) ,-S- halogenation (C1-C8) alkyl group (such as but not limited to-SCF3)、-(C1-C6) heterocyclic radical is (for example but not Be limited to pyrrolidine, oxolane, pyrans or morpholine) ,-(C1-C6) heteroaryl (such as but not limited to tetrazolium, imidazoles, furan, pyrazine Or pyrazoles) ,-phenyl, optionally substituted benzyl ,-NHC (O) O- (C1-C6) alkyl group ,-N ((C1-C6) alkyl) C (O) O- (C1-C6) alkyl group ,-C (=NH)-(C1-C6) alkyl group ,-C (=NOH)-(C1-C6) alkyl group or-C (=N-O- (C1-C6) alkyl)-(C1-C6) alkyl group.
Term " test kit (kit) " as used herein refers to the product packed, and the product of this packaging comprises multiple groups Point, can with these components and the present invention there is the compound of chemical formula (I) together with apply, disorderly for treating autoimmune Disorderly.This test kit preferably comprises box or the container accommodating the component of this test kit.This box or container paste labelling or The scheme of FDA's approval.This box or the component of the container receiving present invention, these components are preferably contained in moulds In material, polyethylene, polypropylene, ethylene or propylene vessel.These vessel are probably pipe with cover or bottle.This test kit is also The compound that can comprise there is chemical formula (I) be described book.
One or more compound of the present invention can be given to human patientses or with drug regimen by their own The form of thing is given, and wherein in pharmaceutical composition, these compounds are to treat or to improve disease as described in this or disease The dosage of disease is mixed with biologically suitable carrier or one or more excipient.The mixture of these compounds also can be with list One mixture or be given to patient in the form of the suitable pharmaceutical composition by formula manufacture.Treatment effective dose refers to It is enough to produce the prevention of disease as described in this or disease or this compound of mitigation or the amount of these compounds.Can be Reference well known within the skill of those ordinarily skilled is inner to be found the preparation of compound of this instant application and gives technology, such as " thunder The medical science of bright " (" Remington's Pharmaceutical Sciences "), mark publishes company limited (Mack Publishing Co.), Easton (Easton), PA, latest edition.
The approach that suitably gives can for example be included：Oral, eye drip, rectum, through mucous membrane, locally or enteral gives；Intestinal Deliver outside stomach, including：Intramuscular, subcutaneous, intramedullary injection, together with intrathecal, direct ventricle be interior, intraperitoneal, intranasal or intraocular injection.
Alternately, with local rather than systematic mode, this compound can be given, for example, by changing this Compound is injected directly into edematous site, often in the form of being in long-acting or extended release formulations.
In addition, giving of this medicine can be carried out with targeted drug delivery system, for example, with endothelial cell specific antibodies In the liposome of coating.
The pharmaceutical composition of the present invention can according to per se known manner (for example, by conventional mixing, dissolving, Pelletize, make the methods such as coated tablet, finely ground, emulsifying, encapsulated, embedding or lyophilizing) it is prepared.
(can be included using one or more physiologically acceptable carrier according to pharmaceutical composition used in the present invention Excipient and auxiliary agent, they promote is processed into pharmaceutically usable several formulations by these reactive compounds) with routine side Formula is prepared.Suitable preparation gives approach depending on selected.
For injection, the reagent of the present invention can be prepared in aqueous solution, preferably buffers in physiological compatibility In liquid, such as hanks (Hanks') solution, Green's Si (Ringer's) solution or normal saline buffer solution.For wearing mucosa Give, using being suitable for the penetrating agent that there is obstacle to be infiltrated in this preparation.These penetrating agent are well known in the art.
For being orally administered to, can easily pass through pharmaceutically to connect these reactive compounds with well known in the art The carrier combinations being subject to are preparing these compounds.These carriers enable these compound tablets, pill, sugar-coats of the present invention Ball, capsule, liquid, colloid, syrup, medicine slurry, suspension are prepared with similar form, so that the patient's mouth that will be treated Clothes picked-up.Pharmaceutical preparations for oral use can be obtained by following steps：By reactive compound and solid excipient phase Mixing, optionally grind the mixture obtaining, and add suitable auxiliary agent after process granular mixture ,if needed, Tablet or coated tablet core can be obtained.Specifically, suitable excipient is filler, for example saccharide, including Lactose, sucrose, Mannitol or Sorbitol；Cellulose preparation, for example, for example, corn starch, wheaten starch, rice starch, potato starch, bright Glue, Tragacanth, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium carbon epoxide methylcellulose and/or Polyvinylpyrrolidone (PVP).If necessary, disintegrating agent class can be added, such as crospolyvinylpyrrolidone, agar or alginic acid or a kind of its salt As sodium alginate.
Coated tablet core is provided with suitable coating.For this purpose, it is possible to use the sugar juice of concentration, wherein these Sugar juice can optionally comprise Radix Acaciae senegalis, Muscovitum, Polyvinylpyrrolidone, Ka Bobo gel, Polyethylene Glycol and/or Titanium dioxide, paint solution and suitable organic solvent or solvent mixture.Dyestuff or coloring agent can add to described tablet or sugar-coat In ball coating, for differentiating or representing the various combination of active compound doses.
The pharmaceutical preparation of orally available use include the plug-in type capsule (push-fit capsule) being made up of gelatin and The sealed soft capsule being made up of gelatin and a kind of plasticizer (as glycerol or Sorbitol).Plug-in type capsule class can contain and filling Agent (as Lactose), binding agent class (as starch based), and/or lubricant class (as Pulvis Talci or magnesium stearate) and, optionally The various active composition of stabilizer class phase mixing.In soft capsule, reactive compound may be dissolved or suspended in suitable liquid, For example in fatty oil, liquid paraffin or liquid macrogol.Additionally, stabilizer also can be added.All for joining of being orally administered to Product should be in suitable such dosage giving.
Buccal is given, these compositionss can take the form of the tablet prepared in a usual manner or lozenge.
For being given by suction, for these compounds in accordance with the purpose of the invention, using a kind of suitable Suitable propellant (e.g., dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other suitable gases) Easily the form being in the spray representing from booster-type packaging or aerosol apparatus is delivered.With regard to pressurized aerosol Speech, dosage device can be determined by the amount providing valve to deliver metering.Can prepare and for example be used in inhaler or insufflator Used in gelatine capsule or cartridge case, these capsules or cartridge case comprise this compound and a kind of suitable powdered substrate (as Lactose Or starch) mixture of powders.
These compounds can be formulated as being entered by injecting (for example, by bolus injection or continuous infusion) Row parenteral gives.Preparation for injection can be existed with unit dosage forms, such as in the ampoule being added with preservative Or in multi-dose container.These compositionss can be using the suspension being such as in oiliness or aqueous carrier, solution or emulsion Form, and preparation reagent can be contained, such as suspending agent, stabilizer and/or dispersant.
The pharmaceutical preparation giving for parenteral includes the aqueous solution agent of the reactive compound in water-soluble form.Separately Outward, the suspension of described reactive compound can be prepared as suitable oily injection suspensions.Suitable lipophilic solvent or carrier Including the fatty acid ester such as ethyl oleate or triglyceride of fatty oil such as Oleum sesami or synthesis, or it is liposome.Aqueouss Injectable suspensions can comprise material such as sodium carboxymethyl cellulose, Sorbitol or the glucosan increasing the viscosity of this suspension.Appoint Selection of land, this suspension also can comprise suitable stabilizer or increase the dissolubility of compound to allow to prepare high enrichment solution Reagent.
Alternately, this active component can be at before use powder type with suitable vehicle (for example aseptic nothing Pyrogen water) group structure.
These compounds also can be formulated into rectal compositions species (as suppository or enema,retention), for example, comprise multiple normal The suppository base (as cocoa butter or other glyceride types) of rule.
In addition to preparation described above, these compounds also can be formulated into a kind of depot formulation.Such long-acting Preparation can be given by implantation (for example through subcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, these chemical combination Thing can be with suitable polymer or hydrophobic material (for example, as the Emulsion in a kind of acceptable oil) or amberlite Fat carries out preparing or being formulated into slightly solvable derivant together, for example, be formulated into a kind of slightly solvable salt.
Example for the pharmaceutical carrier of hydrophobic compound of the present invention is co-solvent system, this system include benzyl alcohol, Non-polar surfactant, the organic polymer that can mix with water and aqueous phase.This co-solvent system can be VPD cosolvent system System.VPD is 3%w/v benzyl alcohol, 8%w/v non-polar surfactant's polysorbate80 and 65%w/v Liquid Macrogol Solution, supply volume with dehydrated alcohol.This VPD co-solvent system (VPD:5W) by with 5% dextrose 1 in aqueous:1 The VPD composition of dilution.This co-solvent system can dissolve hydrophobic compound well, and this in whole body give when produce Hypotoxicity.Naturally, the ratio of co-solvent system can occur sizable change, and does not destroy its dissolubility and toxicity feature. In addition, the identity of this co-solvent component can be different：For example, it is possible to use the surfactant of other low-toxicity nonpolar Rather than polysorbate80；The fractionated dose of Polyethylene Glycol can be different；The compatible polymer of other biological can replace For Polyethylene Glycol, such as Polyvinylpyrrolidone；And other saccharides or polysaccharide can replace dextrose.
Alternately, other can be adopted to be used for the delivery system of hydrophobic pharmaceutical compounds.Liposome and Emulsion are to use In the example known to the delivery vehicle of hydrophobic drug or carrier.Some organic solvents, for example, can also adopt dimethyl Sulfoxide is although usual cost is that have bigger toxicity.Additionally, it is possible to use slow-released system conveys these compounds, for example Comprise the semipermeability substrate of the solid hydrophobic polymers of therapeutic agent.Have built up diversified slow-release material, these delay It is well known to those skilled in the art for releasing material.Depending on their chemical property, slow releasing capsule can discharge these compounds Several weeks are up to more than 100 days.Chemical property depending on this therapeutic agent and biological stability, can for protein stabilization With using other strategy.
These pharmaceutical compositions can also comprise suitable solid or gel phase carriers or excipient.These carriers or figuration The example of agent includes but is not limited to Calcium Carbonate, calcium phosphate, various saccharide, starch, cellulose derivative, gelatin and polymer (example As Polyethylene Glycol).
Many in the compounds of this invention can be provided as the salt of the ion balance with pharmaceutically compatible.Can use Many acid form the salt of pharmaceutically compatible, including but not limited to hydrochlorate, sulfur salt, acetate, lactate, tartrate, Herba Marsileae Quadrifoliae Fruit acid salt, succinate etc..These salt are more soluble in aqueouss or the solvent of other protons than corresponding free alkali form.
The pharmaceutical composition being suitable in the present invention using includes following compositionss, and wherein said composition comprises the work of effective dose Property composition is to realize its target.More specifically, therapeutically effective amount refers to effectively prevent and treat the experimenter being treated The existing Symptomatic amount developing or mitigate this symptom.Determine effective dose completely in the limit of power of those skilled in the art.
For any compound using in the methods of the invention, initially can estimate to treat effective agent from raji cell assay Raji Amount.For example, it is possible to prepare dosage in cell and animal model to realize circulation composition scope, this scope is included as surveyed in cell The IC determining in fixed50(for example, realizing the concentration of the test compound of half maximum suppression of given protein kinase activity).One In the case of a little, it is suitable for when there is 3% to 5% serum albumin determining IC50, because this determination is verified close to plasma protein being somebody's turn to do The combination effect of compound.Can be using this type of information more accurately to determine the useful dosage in the mankind.In addition, for complete The most preferred compound that body gives effectively suppression is in the level that can safely realize in blood plasma in complete cell Protein kinase signal transduction.
Treatment effective dose refers to lead to the amount of the compound of patients symptomatic's improvement.The toxicity of these compounds and curative effect It is determined by the standard pharmaceutical procedures in cell culture or laboratory animal, for example, for determining maximum tolerated dose And ED (MTD)50(effective dose of 50% maximum reaction).Dose ratio between poisonous effect and curative effect is therapeutic index by table Reach for MTD and ED50Between ratio.Preferably show the compound of high therapeutic index.Dosage range used in being formulated in the mankind When, it is possible to use the data obtaining from these cell culture mensure and zooscopy.The dosage of these compounds is preferably located in Including having little or avirulent ED50Circulation composition in the range of.This dosage can change in the range of this, depending on employing Dosage form and using give approach.Definite preparation can be selected, give way by the situation of individual physician in view patient Footpath and dosage (see, e.g., Fen Geer (Fingl) et al., 1975, in therapeutic pharmacological basis (The Pharmacological Basis of Therapeutics) in, Ch.1, p.1).In the treatment of critical days it may be necessary to Close to MTD acute inject or irrigate give to obtain fast reaction.
Can individually regulating dosage and interval to provide the blood plasma level of following active part, this level be enough to remain sharp Enzyme regulation, or minimal effective concentration (MEC).For every kind of compound, this MEC can different but can be from vitro data Estimated；For example realize the required concentration of 50%-90% protein kinase suppression using mensure described here.Realize this MEC Necessary dosage will depend upon the feature of individuality and gives approach.However, it is possible to use HPLC measures or bioassay comes really Determine plasma concentration.
Spacing of doses can be determined using MEC value.Using following scheme, compound is given, the program maintains blood plasma Level reaches the time of 10%-90% higher than MEC, preferably between 30%-90%, and most preferably 50%-90% it Between, until realizing the preferable improvement of symptom.Administer locally to or selective absorbing in the case of, effective local concentration of this medicine May be unrelated with plasma concentration.
The amount of the compositionss giving will be of course depend upon treated experimenter, the body weight of experimenter, ailing serious journey Spend, give mode and the judgement of the doctor writing a prescription.
If necessary, these compositionss may be presented in packaging or dispenser device, this packaging or dispenser device can The one or more unit dosage forms containing active component can be included.This packaging may, for example comprise metal or plastic sheeting (for example Blister package).This packaging or dispenser device may be with being described.Can be to the bag prepared in compatible pharmaceutical carrier The compositionss of the compound containing the present invention are prepared, are placed in suitable vessel and stick for treating specified disease Label.
In some preparations, in the form of very undersized granule, the compound using the present invention is beneficial, example As such as obtained by comminution by gas stream.
In the manufacture of pharmaceutical composition, the use of the compound of the present invention is illustrated by following description.At this In description, term " reactive compound " indicates any compound of the present invention but the end-product of specifically one of following instance Any compound.
A) capsule
In the preparation of capsule, the Lactose solution coalescence of the reactive compound of 10 weight portions and 240 weight portions can be blended. This mixture can be filled in hard gelatin capsule, and each capsule comprises the unit dose of reactive compound or unit dose Part.
B) tablet
For example tablet can be prepared from following component.
Weight portion
This reactive compound, this Lactose and some starch can be carried out depolymerization, blending, and by the mixture obtaining with The solution of the Polyvinylpyrrolidone in ethanol makes granule together.Can be by the granule being dried and magnesium stearate and remaining shallow lake Powder is blended.Then this mixture is compressed to provide tablet in tablet machine, each tablet comprises the unit dose of reactive compound Amount or the part of unit dose.
C) enteric coated tablet
Tablet can be prepared by above-mentioned method in (b).Can be by these tablets by using 20% O-phthalic Sour cellulose acetate and 3% diethyl phthalate are in ethanol:Dichloromethane (1:1) solution in is carried out in a conventional manner Enteric coating.
D) suppository
In the preparation of suppository, for example, it is possible to the reactive compound of 100 weight portions is incorporated to the glycerol three of 1300 weight portions Form suppository, each suppository comprises the therapeutically effective amount of active component in acid esters suppository base and by this mixture.
In the present compositions, if it is desired, what this reactive compound can be compatible with other pharmacologically has work Property composition associate.For example, it is possible to by the compound of the present invention and another kind be known to be for treat disease described here or The therapeutic combination of disease is given.For example, the therapeutic combination other with one or more, the suppression of this reagent or prevention The intracellular reaction of the generation of VEGF or angiogenin, weakening VEGF or angiogenin, blocking-up Cellular Signaling Transduction Mediated, suppression Vascular permeability processed is too high, reduce inflammation or suppression or the formation of prevention edema or new vesselses.The compound of the present invention can So that before other therapeutic agent, give afterwards or concurrently, the process which kind of gives is all suitable.Other Therapeutic agent includes but is not limited to, consumer edema sex steroid, NSAID, ras inhibitor, anti-TNF agent, anti-IL1 agent, antihistamine, PAF- antagonist, COX-1 inhibitor, cox 2 inhibitor, NO synthase inhibitor, Akt/PTB inhibitor, IGF-1R inhibitor, Pkc inhibitor, PI3 kinase inhibitor, calcineurin inhibitors and immunosuppressant.The compound of the present invention and other controlling Treat agent to act in additive manner or synergistically.Therefore, compared with individually giving with arbitrary material, suppression angiogenesis, vascular permeability mistake The giving of such combination of material that high and/or suppression edema is formed can larger mitigate hyperplasia sexual disorder, blood vessel life Become, vascular permeability is too high or the misery of the illeffectss of edema.In the treatment of Malignant disorders, with anti-proliferate or cell toxicant The combination of property chemotherapy or radiation is within the scope of the present invention.
The present invention also comprises the purposes as medicament for the compound with chemical formula (I).
Another aspect provides for treating that vascular permeability is too high, angiogenesis-dependent disease, increasing Natural disposition disease and/or in the manufacture of the medicament of the immune system disorder in mammal (specifically, the mankind), has chemical formula (I) compound and its purposes of salt.
Present invention provides treatment vascular permeability is too high, incorrect neovascularization, proliferative disease and/or immunity System disorders, the effectively treatment amount that the method includes the compound by having chemical formula (I) is (concrete to mammal in need Ground, the mankind) given.
Abbreviation
In vitro BTK kinase activity is measured by time-resolved fluorescence Resonance energy transfer (trFRET)
Internal BTK corresponds to recombined human catalytic domain (aa393-659), and this catalytic domain is with having N- end his labelling in SF9 Express in cell and purification is carried out by immobilization metal affinity chromatography.By BTK and peptide substrates under different inhibitor concentration (biotin-TYR1, sequence：Biotin (Biotin)-(Ahx)-GAEEEIYAAFFA-COOH, 0.4 μM of ultimate density) following Mix in reaction buffer：50mM MOPSO pH6.5、10mM MgCl2、2mM MnCl2, 2.5mM DTT, 0.01%BSA, 0.1mM Na3VO4With 0.01mM ATP.After being incubated about 60min at room temperature, by adding EDTA (ultimate density：100mM) will This reactant is quenched and adds detectable (final approximate concentration：30mM HEPES pH 7.0,0.06%BSA, 0.006% tells Warm (Tween) -20,0.24M KF, (the antiphosphotyrosine antibody cat#61T66KLB of europium labelling is cis for 80ng/mL PT66K Biotech firm (Cisbio), Bedford (Bedford), MA) and 0.6 μ g/mL SAXL (algae chain (Phycolink) strepto- parent With element-allophycocyanin receptor, cat#PJ25S, Pu Luomei company (Prozyme), holy profit ARIXTRA (San Leandro), CA) enter Row chromogenic reaction.It is incubated this chromogenic reaction about 60min in the dark at room temperature, then by using the 337nm for exciting The laser launch wavelength monitored at 665nm is entered via time-resolved fluorescence detector (asteria (Rubystar), BMG) Row reading.In the range of this setting-out line, the signal observed at 665nm is directly related with Phosphorylated products and can For calculating IC50Value.
In vitro CSF-1R kinase activity is measured by time-resolved fluorescence Resonance energy transfer (trFRET)
CSF-1R construct corresponds to recombinant human catalytic domain (aa538-910), and this construct is from hero company (Invitrogen) (cat#PV4092) buys.Under different inhibitor concentration by CSF-1R and peptide substrates (biotin- TYR1, sequence：Biotin (Biotin)-(Ahx)-GAEEEIYAAFFA-COOH, 0.4 μM of ultimate density) in following reaction buffering Mix in liquid：50mM MOPSO pH 6.5、10mM MgCl2、2mM MnCl2, 2.5mM DTT, 0.01%BSA, 0.1mM Na3VO4With 0.01mM ATP.After being incubated about 60min at room temperature, by adding EDTA (ultimate density：100mM) this is reacted Thing is quenched and adds detectable (final approximate concentration：30mM HEPES pH 7.0,0.06%BSA, 0.006% tween (Tween) -20,0.24M KF, 80ng/mL PT66K (the cis life of antiphosphotyrosine antibody cat#61T66KLB of europium labelling Thing company (Cisbio), Bedford (Bedford), MA) and 0.6g/mL SAXL (algae chain (Phycolink) strepto- is affine Element-allophycocyanin receptor, cat#PJ25S, Pu Luomei company (Prozyme), holy profit ARIXTRA (San Leandro), CA) carry out Chromogenic reaction.It is incubated this chromogenic reaction about 60min in the dark at room temperature, then swash by using the 337nm for exciting The light launch wavelength monitored at 665nm is carried out via time-resolved fluorescence detector (asteria (Rubystar), BMG) Reading.In the range of this setting-out line, the signal observed at 665nm is directly related with Phosphorylated products and can use In calculating IC50Value.
For with the purpose of following table and example, Btk the or CSF-1R IC of every kind of compound50Value is expressed as follows：A=IC50 Compound less than 0.1 μM, B=IC50Compound in the range of 0.1 μM to 1 μM and C=Btk IC50At 1 μM to 50 μM In the range of compound.NT=does not test
All lists of references, including magazine article, patent and disclosed patent application teachings all pass through to quote with It is combined in full.
Following instance is for explanatory purposes and to should not be construed as limited to the scope of the present invention.
General synthetic scheme
The compound of the present invention can be prepared by using synthesis conversion (as shown in scheme I-IV).Initial Material is commercially available, by program described here, literature procedure or can would is that organic chemistry filed ordinary skill people Program known to member (see, e.g., Lan Ruoke, R.C. (Larock, R.C.) " comprehensive organic conversion:Functional group prepares to refer to South, the second edition " (" Comprehensive Organic Transformations:A Guide to Functional Group Preparations,2ndEdition "), 1999, Willie-VCH (Wiley-VCH) or Green, T.W. (Greene, T.W.) and 5 Hereby, P.G.M. (Wuts, P.G.M.) " protection group in organic synthesiss, the third edition " (" Protective Groups in Organic Synthesis,3rdEdition "), 1999, Willie international scientific (Wiley-Interscience)) it is prepared. The method of [1,2,4] triazole [1,5-a] pyrazine -8- amines of the preparation present invention is shown in scheme I.6,8- bis- bromo- [1,2, 4] triazole [1,5-a] pyrazine 1 is commercially available (such as Noah's ark drugmaker (Ark Pharm)) and can be by using ability Condition known to the those of ordinary skill of domain (as described in general program A) passes through displacement chemistry or by as general journey Palladium mediated chemistry described in sequence B is reacted with amine to provide compound 2.Can be from compound 2 and commercially available boric acid or boric acid Salt or be coupled with from the Suzuki that such as in Lan Ruoke, the borate of the halogenide preparation described in R.C. (above-mentioned) is carried out React (such as general program C) to obtain compound 3.If necessary, using reaction (example known to persons of ordinary skill in the art If blue visitor as mentioned above, R.C. (Larock, R.C.)) carry out the further of [1,2,4] triazole [1,5-a] pyrazine -8- amine 3 Functionalization.For example, it is possible to a double bond will be comprised by using hydrogenation conditions (those for example described in general program E) Triazole pyrazine 3 is reduced into saturation system.In addition, amide (for example general journey can be prepared from the triazole pyrazine 3 comprising primary amine or secondary amine Sequence F).Further, by using Green as mentioned-above, T.W. (Greene, T.W.) and 5 hereby, P.G.M. (Wuts, P.G.M. those conditions in) or described in general program D are carried out to the triazole pyrazine 3 comprising shielded primary amine or secondary amine Deprotection.For example, for the R ' comprising blocking group (such as Boc group), this blocking group can be removed and do not protected with producing Shield amine (such as general program D) and and then this de-protected compound 3 can be other reacted as described abovely.
Scheme I
The method of [1,2,4] triazole [1,5-a] pyridine -8- amines of the preparation present invention is shown in scheme II.Use Those conditions for example described in example #1, step A, by commercially available 2- amino -3- bromo- 5- chloropyridine 4 (such as Noah's ark system Medicine company) react to provide intermediate 5 with DMF-DMA, then by this intermediate be cyclized be given the bromo- 6- of 8- chloro- [1,2, 4] triazole [1,5-a] pyridine 6.By palladium mediated condition known to persons of ordinary skill in the art (as retouched in general program B Those conditions stated) chloro- for bromo- for 8- 6- [1,2,4] triazole [1,5-a] pyridine 6 is reacted with amine to provide compound 7.Can be from Compound 7 and commercially available boric acid or borate or with from such as in Lan Ruoke, R.C. (above-mentioned) or general program H The Suzuki coupling reaction (such as general program C) that the borate of the halogenide preparation of description is carried out obtains compound 8.Alternative Ground, can be by using the different approach synthesis compounds 8 being shown in scheme IIa.Using for example in example #4, step A Those conditions of description, with if the mode similar to step A of example #1 is by bromo- for commercially available 5- 3- chloropyridine -2- amine 12 (example As Noah's ark drugmaker) it is converted into the bromo- 8- of 6- chloro- [1,2,4] triazole [1,5-a] pyridine 13.Can from compound 13 with can business The boric acid of purchase or borate or with from the halogenide such as in Lan Ruoke, described in R.C. (above-mentioned) or general program H The Suzuki coupling reaction that the borate of preparation is carried out realizes the synthesis of compound 14.By known to persons of ordinary skill in the art Palladium mediated condition (condition as described in general program B) reacts compound 14 and amine to provide compound 8.As Fruit needs, and carries out [1,2,4] using reaction known to persons of ordinary skill in the art (if blue visitor for example above-mentioned, R.C.) The further functionalization of triazole [1,5-a] pyridine -8- amine 8.For example, it is possible to by using hydrogenation conditions (for example in general program E Described in those) the triazole pyridine 8 comprising a double bond is reduced into saturation system.Furthermore it is possible to from comprising primary amine or secondary Amide (such as general program F) prepared by the triazole pyridine 8 of amine.Further, by using Green as mentioned-above, T.W. (Greene, T.W.) and 5 hereby, those conditions in P.G.M. (Wuts, P.G.M.) or described in general program D are to comprising The triazole pyridine 8 of shielded primary amine or secondary amine is deprotected.For example, for comprising blocking group (such as Boc group) R ', can remove this blocking group to produce unprotected amine (such as general program D) and and then this de-protected chemical combination Thing 8 can be other reacted as described abovely.
Scheme II
Scheme IIa
The method of [1,2,4] triazole [1,5-a] pyrazine -8- amines of the preparation present invention is shown in scheme III.6,8- Dibromo imidazo [1,2-a] pyrazine 9 is commercially available (such as Noah's ark drugmaker) and can be common by using this area Condition (as described in general program A) known to the skilled person passes through displacement chemistry or by as in general program B The palladium mediated chemistry of description is reacted with amine to provide compound 10.Can from compound 10 and commercially available boric acid or borate or Person and the Suzuki coupling reaction carrying out from the borate that such as in Lan Ruoke, prepared by the halogenide described in R.C. (above-mentioned) (such as general program C) is obtaining compound 11.If necessary, using reaction known to persons of ordinary skill in the art (for example If blue visitor above-mentioned, R.C.) carry out the further functionalization of imidazo [1,2-a] pyrazine -8- amine 11.For example, it is possible to it is logical Cross and using hydrogenation conditions (for example those are described in general program E), the Imidazopyrazines 11 comprising a double bond are reduced into Saturation system.Furthermore it is possible to prepare amide (such as general program F) from the Imidazopyrazines 11 comprising primary amine or secondary amine.Further, By using Green as mentioned-above, T.W. (Greene, T.W.) and 5 hereby, in P.G.M. (Wuts, P.G.M.) or Those conditions described in general program D deprotect to the Imidazopyrazines 11 comprising shielded primary amine or secondary amine.Example As for the R ' comprising blocking group (such as Boc group), this blocking group can be removed to produce unprotected amine (example As general program D) and and then this de-protected compound 11 can be other reacted as described abovely.
Scheme III
The method of imidazo [1,2-b] pyridazine compound of the preparation present invention is shown in scheme III.8- bromo- 6- chlorine imidazoles And [1,2-b] pyridazine 12 is commercially available (such as Ai Site company (AstaTech)) and can be common by using this area Condition (as described in general program A) known to the skilled person passes through displacement chemistry or by as in general program B The palladium mediated chemistry of description is reacted with amine to provide compound 13.Can from compound 13 and commercially available boric acid or borate or Person and the Suzuki coupling reaction carrying out from the borate that such as in Lan Ruoke, prepared by the halogenide described in R.C. (above-mentioned) (such as general program C) is obtaining compound 14.If necessary, using reaction known to persons of ordinary skill in the art (for example If blue visitor above-mentioned, R.C.) carry out the further functionalization of imidazo [1,2-b] pyridazine -8- amine 14.For example, it is possible to it is logical Cross and using hydrogenation conditions (those for example described in general program E), the Imidazopyridazine 14 comprising a double bond is reduced into Saturation system.Furthermore it is possible to prepare amide (such as general program F) from the Imidazopyrazines 14 comprising primary amine or secondary amine.Further, By using Green as mentioned-above, T.W. (Greene, T.W.) and 5 hereby, in P.G.M. (Wuts, P.G.M.) or Those conditions described in general program D deprotect to the Imidazopyridazine 14 comprising shielded primary amine or secondary amine.Example As for the R ' comprising blocking group (such as Boc group), this blocking group can be removed to produce unprotected amine (example As general program D) and and then this de-protected compound 14 can be other reacted as described abovely.
Scheme IV
General program and example
Be used for build in this specification disclose majority of compounds General synthetic scheme described in scheme 1-9 such as Under.These schemes are provided merely for illustrative purpose and are not construed as limitation of the scope of the invention.
Scheme 1：Aryl or the nucleophilic displacement of fluorine (general program A) of hetaryl halogenides and amine
Scheme 2：Aryl or hetaryl halogenides are anti-with the Buchwald-Hartwig (Buchwald-Hartwig) of amine Answer (general program B)
Scheme 3：Aryl or hetaryl halogenides and boric acid or boratory reaction (general program C)
Ar-X+R-B(OH)2Or R-B (OR)2→Ar-R
Scheme 4：The acid cleavage (general program D) of the amine protected by Boc
Scheme 5：The hydrogenation (general program E) of double bond
Scheme 6：Form amide from acid chloride and amine or from chloro-formate and amine formation carbamate (general program F)
Scheme 7：The chiral preparative HPLC of stereoisomer separates (general program G)
Scheme 8：Form sulfonamide (general program H) from sulfonic acid chloride and amine
Scheme 9：Form cyanamide (general program I) from amine with Bromine cyanide.
General program list
General program A aryl or the nucleophilic displacement of fluorine of hetaryl halogenides and amine
General program B aryl or hetaryl halogenides are reacted with the Buchwald-Hartwig of amine
General program C aryl or hetaryl halogenides and boric acid or boratory reaction
The acid cleavage of the amine that general program D is protected by Boc
The hydrogenation of general program E double bond
General program F forms amide or from chloro-formate and amine formation carbamate from acid chloride and amine
The chiral preparative HPLC of general program G stereoisomer separates
General program H forms sulfonamide from sulfonic acid chloride and amine
General program I forms cyanamide from amine with Bromine cyanide.
Following instance is ranked up according to general program final used in their preparation.In the appropriate case, lead to Cross and list this general program (letter code) and other reactant or reagent in the bracket after their title in an orderly manner Describe the route of synthesis of any novel intermediates in detail.By using example #F.1.4 as non-limitative illustration, described below The sample of this scheme.Example #F.1.4 be 8- ((6- (1- Antiepilepsirin -3- base)-[1,2,4] triazole [1,5-a] pyrazine - 8- yl) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one, this compound is by using table such as in option A The general program F showing from 8- ((6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro - 1H- benzo [b] azatropylidene -2 (3H) -one is prepared.
Option A
Prepare example #F.1.4,8- ((6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia as follows Base) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one precursor：According to the condition being given in general program A, by Just by bromo- for 6,8- bis- [1,2,4] triazole [1,5-a] pyrazine (drugmaker is commercially available from Noah's ark) and 8- amino -4,5- dihydro - 1H- benzo [b] azatropylidene -2 (3H) -one (commercially available from Ai Site company) is reacted (as shown in option b), to give Go out 8- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) - Ketone, the subsequently condition by using being given in general program C, by the compound obtaining and tert-butyl 3- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- base) -5,6- dihydropyridine -1 (2H)-formic acid esters are (from Ali chemical company (Anichem) commercially available) reacted, to provide tert-butyl 3- (8- ((2- oxo -2,3,4,5- tetrahydrochysenes -1H- benzo [b] Azatropylidene -8- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) -5,6- dihydropyridine -1 (2H)-formic acid esters, subsequently By using the condition providing in general program E, the compound obtaining is reacted with Pd/C, to provide tert-butyl 3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] triazole [1,5-a] pyrazine - 6- yl) piperidines -1- formic acid esters, the subsequently condition by using being given in general program D, will be anti-with TFA for the compound obtaining Should, to provide 8- ((6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one.Therefore synthesize example #F.1.4,8- ((6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -8- base) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one precursor response hierarchy (as detailed above) Preparation and EXAMPLEPART are converted into：8- ((6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia Base) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one is (using A from 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine [Noah's ark drugmaker] and 8- amino -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one [Ai Site company], using C from Tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -5,6- dihydropyridine -1 (2H)-formic acid esters [Ali chemical company], it is prepared using E Pd/C, using D with TFA).
Therefore this example #F.1.4 will be written as：Example #F.1.4 preparation from acryloyl chloride and 8- ((6- (piperidines -3- base) - [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one (by using A is from 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine [Noah's ark drugmaker] and 8- amino -4,5- dihydro -1H- benzo [b] Azatropylidene -2 (3H) -one [Ai Site company], using C from tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxane penta Borine -2- base) -5,6- dihydropyridine -1 (2H)-formic acid esters [Ali chemical company], carried out with Pd/C, using D TFA using E Preparation).In the table after general program, this be by have in the title of table a reactant and with this product be located at same One of row has a reactant to represent in individually arranging.
Option b
Analysis method
Analysis method is included in the table of following procedure, the explanation of general program or example.Unless otherwise stated, watt In peace (Varian) 400Mhz magic angle spining NMR spectroscopy instrument (Mercury Plus), love Novartis (Inova) or 400-MR instrument Upper collection is all of1H NMR data, and chemical shift is quoted with PPM (ppm).Sample is dissolved in chloroform, from Dynamic polariscope, at λ=589nm, researchs and analyses automatic polarimeter IV (Rudolph Reasearch with Rudoiph Analytical Autopol IV) determine optical activity.Using in table 1 provide lower case represent method, LC/MS and HPLC data is with reference to LC/MS and HPLC condition table.The method being represented using the digital alphabet providing in table 2, chiral SFC and HPLC Data is with reference to chiral SFC and HPLC condition.
Table 1.LC/MS and HPLC method
The chiral SFC and HPLC method of table 2.
Purification process
For the example not having detailed program, can be according to any technology known to persons of ordinary skill in the art or skill The combination of art is carrying out the purification of these compounds.Some non-limiting examples include compound (for example, the heptan desired by eluting Alkane, EtOAc, DCM, MeOH, MeCN, water etc.), use fixing phase (for example, silica gel, aluminium oxide etc.) and solvent (or solvent combination) Carry out flash chromatography；Compound (for example, heptane, EtOAc, DCM, MeOH, MeCN, water etc.), with admittedly desired by eluting Determine phase (for example, silica gel, aluminium oxide etc.) and solvent (or solvent combination) is prepared type TLC；Reversed-phase HPLC is (for some non-limits Property condition processed, referring to table 1)；Combination from suitable solvent or solvent (such as MeOH, EtOH, i-PrOH, EtOAc, toluene etc.) Or solvent combination (such as EtOAc/ heptane, EtOAc/MeOH etc.) recrystallization；With fixing phase and appropriate solvent (for some non-limits Property condition processed, referring to table 2) carry out chiral HPLC, with the compound desired by eluting；And have suitable modifying agent (such as MeOH, EtOH, i-PrOH such as DEA, TFA etc. with and without other modifying agent) fixing phase and CO2Carry out chiral SFC；From Solvent combination (such as DMF/ water, DMSO/DCM, EtOAc/ heptane etc.) precipitates；With appropriate solvent (such as EtOAc, DCM, MeCN, MeOH, EtOH, i-PrOH etc.) it is ground；By by compound dissolution in a liquid and with suitably immiscible liquid (example As DCM/ water, EtOAc/ water, DCM/ saturation aqueouss NaHCO3, aqueouss NaHCO of EtOAc/ saturation3, DCM/10% aqueouss HCl, EtOAc/10% aqueouss HCl etc.) washing extracted；Distillation (such as simple distillation, fractional distillation, bulb (Kugelrohr) distillation etc.)； Carry out gas chromatography using suitable temperature, vector gas and flow velocity；Distillation under suitable temperature and pressure；By tool There is medium (the such as aluminium silicate carrier of solvent (such as heptane, hexane, EtOAc, DCM, MeOH etc.) or solvent combinationAluminium oxide, kieselguhrSilica gel etc.) filtration that carries out；With and without solid carrier (resin Base, such as ion exchange) salt formation.Specific salt formation purification process can not be used compound of interest to be carried out point From.For example, in the case that the reversed-phase HPLC with having aqueouss TFA buffer completes purification, this tfa salt can be separated.These Technology some description be found in below with reference to：Gordon, A.J. (Gordon, A.J.) and Ford, R.A. (Ford, R.A.) " changes The companion of scholar " (" The Chemist ' s Companion "), 1972；" experiment has for Pa Lesi, D.R. (Palleros, D.R.) Chemical machine " (" Experimental Organic Chemistry "), 2000；Si Dier, W.C. (Still, W.C.), antiperspirant (Kahn) and M. Mi Tela, A. (M.Mitra, A.) organic chemistry periodical (J.Org.Chem.) 1978,43,2923；Swallow, B. (Yan, B.) " combinatorial chemistry analysis and purification process " (" Analysis and Purification methods in Combinatorial Chemistry "), 2003；Kazakhstan Wood, L.M. (Harwood, L.M.), Moody's, C.J. (Moody, C.J.) and amber west, J.M. (Percy, J.M.) " Experiment of Organic Chemistry:Standard and minute yardstick, the second edition " (" Experimental Organic Chemistry:Standard and Microscale,2ndEdition "), 1999；Si Qieer mayer, J.G. (Stichlmair, J.G.) and Fil, J.R. (Fair, J.R.) " distillation；Principle and put into practice " (" Distillation； Principles and Practices "), 1998；Bi Sili, T.E. (Beesley, T.E.) and Scott, R.P.W. (Scott, R.P.W.) " chiral chromatography " (" Chiral Chromatography "), 1999；Rich in blue Dege, J.A. (Landgrebe, J.A.) " Lab Organic of theory and practice, fourth edition " (" Theory and Practice in the Organic Laboratory,4thEd. "), 1993；In Si Kege, D.A. (Skoog, D.A.) and profit, J.J. (Leary, J.J.) " Instrumental Analysis principle, fourth edition " (" Principles of Instrumental Analysis, 4thEd. "), 1992； G. Sa Bo Raman Buddhist nun Asia (G.Subramanian), " chiral separation technology, the third edition " (" Chiral Separation Techniques,3rdEdition "), 2007；Y. Ka Zhakeweiqi (Y.Kazakevich), R. strangle Bluto (R.Lobrutto), " for the high performance liquid chromatography of pharmaceutical department scholar " (" HPLC for Pharmaceutical Scientists "), 2007.Can optionally be purified by being listed below by using one or more above-mentioned purification process General program preparation intermediate and final compound.
Preparation and example
Unless it is further noted that all of parent material is from Sigma-Aldrich (Sigma- after chemical name Aldrich) (include fluke (Fluka), aldrich Market Selection (Aldrich Market Select) and find CPR (Discovery CPR)) company is commercially available.The reagent being given/reactant title be as on business bottle name or such as IUPAC company,Metachemistry drawing 12.0ChemDraw Ultra 12.0)、Chemical electron notebook 11Chemistry E-Notebook 11) or automatic guide 2000 (AutoNom 2000) generate.Universal synthesis method used in each general program is followed and is included using specified The explanation of the compound of general program synthesis.It is pointed out here that actual conditions and reagent in do not have one kind to be interpreted to the present invention Scope limit and provide these conditions and reagent being merely to illustrate property purpose.Be appointed as salt compound (such as hydrochlorate, Trifluoroacetate) can contain more than this salt of a molar equivalent or the acid that can contain as excipient.The change of the present invention Compound, wherein absolute stereochemical are by using defining on the parent material of commercially available enantiomer-pure or spatial chemistry Intermediate or determined by X-ray diffraction, the asterisk instruction after example number.Otherwise this absolute stereochemical is unknown And be randomly assigned as shown in the figure.
Preparation #1：6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- amine
Step A. methyl 3- nitro -1H- pyrazoles -5- formic acid esters
At 0 DEG C, to 3- nitro -1H- pyrazoles -5- carboxylic acid (69.75g, 444mmol) (Noah's ark drugmaker) in MeOH (1L) add thionyl chloride (84mL, 1154mmol) in solution.At 0 DEG C, then this mixture stir about 20min will It is heated to reflux about 2h.The solution obtaining is concentrated under reduced pressure to provide methyl 3- nitro -1H- pyrazoles -5- formic acid esters (61.25g, 81%)：LC/MS (table 1, method l) Rt=1.42min.；MS m/z:169(M+H)+.
Step B. methyl 1- (2- bromoethyl) -3- nitro -1H- pyrazoles -5- formic acid esters
The 3L 3 neck flask being furnished with reflux condenser and thermocouple is filled with methyl 3- nitro -1H- pyrazoles -5- formic acid esters (75.5g, 441mmol) and DMF (735mL).Cesium carbonate (173g, 529mmol) is added batch-wise and this reaction is heated to about 98 DEG C continue 5min, are subsequently cooled to ambient temperature about 30min.Will before adding glycol dibromide (380mL, 4412mmol) This reaction is cooled to about 0 DEG C in ice bath.This reaction is stirred, is heated to ambient temperature, continues about 5h.By adding phosphoric acid The aqueous solution (120g is in 1L) of potassium dihydrogen is quenched to this reactant mixture.Molten to obtain with EtOAc (3x300mL) Liquid is extracted.This organic moiety merging is dried, is filtered and concentrate under reduced pressure to provide methyl 1- (2- with MgSO4 Bromoethyl) -3- nitro -1H- pyrazoles -5- formic acid esters (120g, 92%)：LC/MS table 1, method l) Rt=2.10min.；MS m/ z:278,280(M+H)+.
Step C. (1- (2- bromoethyl) -3- nitro -1H- pyrazoles -5- base) methanol
Will be configured with charging hopper and under ice bath cooling 3L flask be filled with tetrahydro Lithium biborate (259mL, 518mmol) (2N is in THF) and THF (252mL).In Deca methyl 1- (2- bromoethyl) -3- nitro -1H- pyrazoles -5- formic acid Ester (72g, 259mmol), before the solution in THF (126mL), this reactant mixture is cooled to about 0 DEG C.At ambient temperature By this reaction stir about 2h.By adding aqueouss saturation NaCl (400mL), this reactant mixture is quenched.Use EtOAc (3x400mL) mixture obtaining is extracted.This organic moiety merging is dried, filters and in decompression with MgSO4 Lower concentration is to provide (1- (2- bromoethyl) -3- nitro -1H- pyrazoles -5- base) methanol (56.1g, 87%)：LC/MS (table 1, method l)Rt=1.52min.；MS m/z:250,252(M+H)+.
Step D.2- nitro -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine
2L flask is filled with (1- (2- bromoethyl) -3- nitro -1H- pyrazoles -5- base) methanol (56g, 190mmol) molten Solution is in DMA (747mL).This reaction is heated to about 140 DEG C and lasts about 5h.This reaction is cooled to ambient temperature this is molten Agent concentrates under reduced pressure.By the residue obtaining EtOAc (500mL) and aqueouss saturation NaHCO3(150mL) segmentation between. Extract this aqueous fractions with EtOAc (3x400mL).The organic moiety MgSO that this is merged4Be dried, filter and under reduced pressure Concentrate.Add the Et of 200mL in the residue that this obtains2O is simultaneously collected by filtration this solid to provide 2- nitro -6,7- two Hydrogen -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine (14g, 43.5%).The filtrate obtaining is concentrated under reduced pressure and uses silica gel chromatography Carry out purification to provide 2- nitro -6, (6.5g, 38.4mmol, 20.19% produce 7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine Rate):)：LC/MS (table 1, method l) Rt=1.31min.；MS m/z:170(M+H)+.
Step E.6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- amine
Flask is filled with 10% palladium carbon (2.64g, 2.483mmol).MeOH in being added on EtOAc (300mL) (100mL) with 2- nitro -6, before 7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine (14g, 83mmol), this flask is taken out very Sky is placed under nitrogen atmosphere.By this reaction evacuation and with hydrogen cleaning three times.By this reaction stir about at ambient temperature 16h.By kieselguhrPad filters this catalyst and is washed this compound with the EtOAc of about 300mL.Will This solvent concentrates under reduced pressure to be given, 6,7- dihydros -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (10.9g, 95%)： LC/MS (table 1, method l) Rt=0.61min.；MS m/z:140(M+H)+.
Preparation #2:Tert-butyl 3- (8- ((t-butoxy carbonyl) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine - 2- yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) azetidine -1- formic acid esters
Step A：N- (6- bromo- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1, 4] piperazine -2- amine
The interpolation tert-butyl 6 in microwave reaction bottle, 8- bis- bromo- [1,2,4] triazole [1,5-a] pyridine (1.0g, 3.6mmol, Noah's ark drugmaker), 6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.503g, 3.61mmol, Preparation #1), 1,4- dioxane (12mL), Cs2CO3(2.353g, 7.22mmol), Xantphos (0.104g, 0.181mmol) and Pd2(dba)3(0.165g, 0.181mmol), this reaction bottle nitrogen is rinsed, adds a cover, stirs and in Biotage microwave It is heated to 120 DEG C in reactor and last about 3h.Dilute this reaction with DCM (80mL) and water (50mL).Separate this organic layer to be used in combination Water (50mL), saline (50mL) washing, and be dried with Na2SO4.Filter this organic layer and concentrate under reduced pressure.By this crude product Carrying out purification by the 5%MeOH eluting that silica gel chromatography is used in DCM provides the N- (6- bromo- [1,2,4] in yellow solid Triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.80g, 43%)：LC/MS (table 1, method p) Rt=1.59min.；MS m/z:335/337(M+H)+.
Step B：(6- bromo- [1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- base) t-butyl carbamate
By N- (6- bromo- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine (0.80g, 1.5mmol), BOC2O (1.08mL, 4.65mmol), TEA (0.649mL, 4.65mmol) and DMAP (0.190g, 1.55mmol) mixed liquor in DCM (60mL) is stirred at room temperature overnight.By this organic layer saturation NH4Cl (3x50mL) washs.By this organic layer Na2SO4It is dried, filter and concentrate.By with EtOAc:Petroleum ether (2:1) wash De- silica gel chromatography carries out purification to provide (6- bromo- [1,2,4] triazole [1,5-a] pyridine -8- of white solid to this product Base) (6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (0.53g, 77%)：LC/MS (table 1, method n) Rt=1.73min.；MS m/z:435/437(M+H)+.
Step C：Tert-butyl 3- (8- ((t-butoxy carbonyl) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine - 2- yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) azetidine -1- formic acid esters
Add trimethylchloro-silicane in the mixture of the zinc (0.16g, 2.5mmol) in the DMA in degasification (3mL) under nitrogen Alkane (0.032mL, 0.25mmol) and glycol dibromide (0.032g, 0.17mmol).By this mixture stir about 15min, and Tert-butyl 3- iodo azetidine -1- formic acid esters (0.35g, 1.2mmol) is added by syringe.By the mixture obtaining About 1.5h is stirred at room temperature to form (1- (t-butoxy carbonyl) azetidine -3- base) zinc (II) iodide.By (6- Bromo- [1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino first Tert-butyl acrylate (0.11g, 0.25mmol) is dissolved in DMA (5mL), and degasification about 5min, subsequently adds PdCl2 (dppf) (1- (the tert- generating before (0.013g, 0.017mmol) and copper (I) iodide (0.056g, 0.30mmol) and then interpolation Butoxy carbonyl) azetidine -3- base) zinc (II) iodide solution.This reaction is heated to about 80 DEG C and lasts about 2h.Will This reactant mixture is diluted with EtOAc (40mL) and is filtered by nylon filter.Add water (40mL), layer is separated, will have Machine is washed with saline (3x40mL), and and then uses anhydrous Na2SO4It is dried.Concentrate this solution and this residue is passed through preparation Type-TLC uses DCM and MeOH (40:1) carry out purification, and obtain tert-butyl 3- (8- ((the t-butoxy carbonyl in brown solid Base) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Azetidine -1- formic acid esters (0.07g, 41.5%)：LC/MS (table 1, method q) Rt=1.81min.；MS m/z:512(M+ H)+.
Preparation #3：1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol
Step A：2- methyl isophthalic acid-(4- nitro -1H- pyrazol-1-yl) propan-2-ol
By round-bottomed flask be filled with 4- nitro -1H- pyrazoles (4g, 35.4mmol), 2,2- dimethyl ethylene oxide (5.1g, 70mmol) and Cs2CO3(23g, 70mmol).This reaction is heated to about 90 DEG C and lasts about 12h, be cooled to ambient temperature, mistake Filter, and filtrate is concentrated under reduced pressure.By silica gel chromatography EtOAc:Petroleum ether (10:1 to 3:1) eluting carrys out purification this is thick Material is to provide 2- methyl isophthalic acid-(4- nitro -1H- pyrazol-1-yl) propan-2-ol (4g, 61% yield) of yellow oily.LC/MS (table 1, method w) Rt=0.976min.；MS m/z:182(M+H)+.
Step B：1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol
By round-bottomed flask be filled with 2- methyl isophthalic acid-(4- nitro -1H- pyrazol-1-yl) propan-2-ol (1g, 5.40mmol) and Raney nickel (Raney Nickel) (1g) in THF (40mL).In a hydrogen atmosphere, this reactant mixture is stirred at 20 DEG C Mix about 12h.This reactant mixture is passed through kieselguhrPad filters and concentrates under reduced pressure to provide white solid 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (0.8g, 95% yield).LC/MS (table 1, method w) Rt= 0.155min.；MS m/z:156(M+H)+.
Preparation #4：4- (4- amino -1H- pyrazol-1-yl) -2- methyl butyl- 2- alcohol
Step A：3- hydroxy-3-methyl butyl methane sulfonates
Round-bottomed flask is filled with 3- methyl butyl- 1,3- glycol (10g, 96mmol) and the TEA in DCM (80mL) (20mL, 144mmol).At about 0 DEG C, solution in DCM (50mL) for the methane sulfonyl chloride (12g, 106mmol) is dripped Add to this reactant mixture.The mixture obtaining is stirred at 0 DEG C 4h.Aqueous sodium bicarbonate by this reaction saturation (100mL) dilute.By this organic moiety anhydrous Na2SO4It is dried, filter and concentrate under reduced pressure to provide the 3- of yellow oily Hydroxy-3-methyl butyl methane sulfonates (12g, 66% yield).1H NMR (400MHz, chloroform-d) δ=4.40 (t, J= 7.1Hz, 2H), 3.01 (s, 3H), 1.94 (t, J=7.1Hz, 2H), 1.81 (s, 1H), 1.27 (s, 6H).
Step B：2- methyl -4- (4- nitro -1H- pyrazol-1-yl) butyl- 2- alcohol
Round-bottomed flask is filled with 3- hydroxy-3-methyl butyl methane sulfonates (12g, 66mmol), K2CO3(7.3g, 53.1mmol) with KI (4.4g, 26.5mmol) ACN (250mL).At about 15 DEG C, by 4- nitro -1H- pyrazoles (3g, 26.5mmol) add to this reactant mixture.Then this reaction is heated to about 90 DEG C and lasts about 12h.By this reactant mixture It is cooled to ambient temperature, dilute with water (100mL) and use EtOAc (3x200mL) to extract.The organic moiety that this is merged is with anhydrous Na2SO4It is dried, filter and concentrate under reduced pressure.By silica gel chromatography petroleum ether:EtOAc(30:1 to 1:1) eluting comes This roughage of purification is to provide 2- methyl -4- (4- nitro -1H- pyrazol-1-yl) butyl- 2- alcohol (4.7g, 89% product of yellow oily Rate).LC/MS (table 1, method w) Rt=0.807min.；MS m/z:200(M+H)+.
Step C：4- (4- amino -1H- pyrazol-1-yl) -2- methyl butyl- 2- alcohol
At about 15 DEG C, to 2- methyl -4- (4- nitro -1H- pyrazol-1-yl) butyl- 2- alcohol (0.5g, 2.5mmol) in THF (50mL) add Raney nickel (1g, 17.04mmol) in the solution in.In a hydrogen atmosphere, by this reactant mixture at 15 DEG C Stir about 12h.By kieselguhrPad filters this reactant mixture and concentrates under reduced pressure to provide pale pink solid 4- (4- amino -1H- pyrazol-1-yl) -2- methyl butyl- 2- alcohol (0.36g, 80% yield).LC/MS (table 1, method w) Rt= 0.162min.；MS m/z:170(M+H)+.
Preparation #5：1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles -4- amine
Step A：2,2,6,6- tetramethyl dihydro -2H- pyrans -4 (3H) -one
Round-bottomed flask is filled with 2,6- dimethyl-g -2,5- diene -4- ketone (10g, 72.4mmol) and 1MHCl (100mL, 100mmol).By this reaction at about 40 DEG C stir about 4 days.Extract this reaction with DCM (3x100mL).This is organic Part anhydrous Na2SO4It is dried, filter and concentrate under reduced pressure to provide the 2,2,6,6- tetramethyl dihydro -2H- of yellow oily Pyrans -4 (3H) -one (10g, 62% yield).1H NMR (400MHz, chloroform-d) δ=2.15-2.10 (m, 2H), 1.91-1.87 (m,2H),1.31(s,6H),1.27(s,6H).
Step B：2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- alcohol
At about 0 DEG C, to 2,2,6,6- tetramethyls dihydro -2H- pyrans -4 (3H) -one (2g, 12.8mmol) in MeOH (50mL) NaBH is added batch-wise in the solution in4(0.97g, 25.6mmol).By this reaction at about 0 DEG C stir about 2h.Should Aqueouss NH of reaction saturation4Cl (50mL) dilutes and uses DCM (2x50mL) to extract.By this organic moiety anhydrous Na2SO4Dry Dry, filter and concentrate under reduced pressure be given the 2 of White waxy, 2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- alcohol (1.4g, 48% yield).1H NMR (400MHz, chloroform-d) δ=4.1-4.05 (m, 1H), 1.92-1.87 (m, 2H), 1.71-1.68 (m, 2H),1.25(s,6H),1.23(s,6H).
Step C：2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- methylmethane sulfonate
Round-bottomed flask is filled with 2,2,6,6- tetramethyls tetrahydrochysene -2H- pyrans -4- alcohol (5.5g, 34.8mmol) and in DCM (110mL) TEA (7.0g, 69mmol) in.At about 0 DEG C, through 20min by methane sulfonyl chloride (5.9g, 52.1mmol) lentamente add to reactant mixture.Through 30min, this reaction is heated to about 20 DEG C, and stirs at about 20 DEG C Mix about 2h.This reactant water (100mL) is diluted and use DCM (3x100mL) to extract.By this organic moiety anhydrous Na2SO4 It is dried, filter and concentrate under reduced pressure to provide the 2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- methylmethane sulphur of yellow oily Hydrochlorate (8g, semifinished product).1H NMR (400MHz, chloroform-d) δ=5.1-5.09 (m, 1H), 3.03 (s, 3H), 2.1-2.07 (d, 2H),1.59-1.54(d,2H),1.30(s,6H),1.25(s,6H).
Step D：4- nitro -1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles
Round-bottomed flask is filled with 4- nitro -1H- pyrazoles (1.2g, 10.61mmol), 2,2,6,6- tetramethyl tetrahydrochysene -2H- Pyrans -4- methylmethane sulfonate (7.5g, 31mmol) and the Cs in DMF (30mL)2CO3(6.9g, 21.2mmol).This is anti- 130 DEG C should be heated to about and last about 12h.This reaction is cooled to ambient temperature, is diluted and used EtOAc with water (100mL) (3x100mL) extract.By this organic moiety anhydrous Na2SO4It is dried, filter and concentrate under reduced pressure.Used by silica gel chromatography Petroleum ether/EtOAc (20:1 to 5:1) eluting carrys out this roughage of purification to provide the 4- nitro -1- (2,2,6,6- of white solid Tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles (0.6g, 21% yield).LC/MS (table 1, method w) Rt=1.37min.； MS m/z:254(M+H)+.
Step E：1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles -4- amine
Exist to 4- nitro -1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles (0.3g, 1.18mmol) Add Raney nickel (1g, 17.04mmol) in solution in THF (20mL).In a hydrogen atmosphere, by this reactant mixture at 20 DEG C Lower stir about 12h.By kieselguhrPad filters this reactant mixture and concentrates white solid to provide under reduced pressure 1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- the base) -1H- pyrazoles -4- amine (0.25g, 85% yield) of body.LC/MS (table 1, method w) Rt=0.729min.；MS m/z:224(M+H)+.
Preparation #6：(trans) -4- (4- amino -1H- pyrazol-1-yl) Hexalin and (cis) -4- (4- amino -1H- pyrrole Azoles -1- base) Hexalin
Step A：4- hydroxy-cyclohexyl methane sulfonates
Round-bottomed flask is filled with hexamethylene-Isosorbide-5-Nitrae-glycol (10g, 86mmol) and the TEA in THF (200mL) (8.7g, 86mmol).At about 0 DEG C, through 20min, methane sulfonyl chloride (3.9g, 34mmol) is lentamente added to anti- Answer in mixture.This reaction is heated to about 20 DEG C, stir about 2h.This reaction water (150mL) is diluted and uses EtOAc (3x150mL) extract.By this organic moiety anhydrous Na2SO4It is dried, filter and concentrate under reduced pressure to provide yellow oily 4- hydroxy-cyclohexyl methane sulfonates (6g, 32% yield).1H NMR (400MHz, chloroform-d) δ=4.8-4.71 (m, 1H), 3.79-3.73(m,1H),3.02(s,3H),2.1-1.97(m,4H),1.6-1.46(m,4H).
Step B：(trans) -4- (4- nitro -1H- pyrazol-1-yl) Hexalin and (cis) -4- (4- nitro -1H- pyrazoles - 1- yl) Hexalin
Round-bottomed flask is filled with 4- nitro -1H- pyrazoles (2g, 17.6mmol), 4- hydroxy-cyclohexyl methane sulfonates (6g, 30.9mmol) and the Cs in DMF (60mL)2CO3(11.5g, 35.4mmol).This reaction is heated to about 130 DEG C hold Renewed treaty 12h.This reactant is cooled to ambient temperature and concentrates under reduced pressure.By silica gel chromatography petroleum ether/EtOAc (10:1 to 1:1) eluting come this roughage of purification be given (trans) -4- (4- nitro -1H- pyrazol-1-yl) Hexalin (0.3g, 8% yield), LC/MS (table 1, method w) Rt=1.08min.；MS m/z:211(M+H)+(cis) -4- (4- nitro -1H- pyrrole Azoles -1- base) Hexalin (0.3g, 8% yield).).LC/MS (table 1, method w) Rt=1.09min.；MS m/z:211(M+H)+
Step C：(trans) -4- (4- amino -1H- pyrazol-1-yl) Hexalin
To (trans) -4- (4- nitro -1H- pyrazol-1-yl) Hexalin (0.15g, 0.71mmol) in THF (15mL) Add Raney nickel (0.3g) in solution.In a hydrogen atmosphere, by this reactant mixture at 20 DEG C stir about 3h.By kieselguhrPad filter this reactant mixture and concentrate under reduced pressure with white solid is provided (trans) -4- (4- amino - 1H- pyrazol-1-yl) Hexalin (0.13g, 91% yield).LC/MS (table 1, method w) Rt=0.162min.；MS m/z:182 (M+H)+.
Step D：(cis) -4- (4- amino -1H- pyrazol-1-yl) Hexalin
To (cis) -4- (4- nitro -1H- pyrazol-1-yl) Hexalin (0.15g, 0.71mmol) in THF (15mL) Add Raney nickel (0.3g) in solution.In a hydrogen atmosphere, by this reactant mixture at 20 DEG C stir about 3h.By kieselguhrPad filters this reactant mixture and concentrates under reduced pressure to provide (cis) -4- (4- amino -1H- of white solid Pyrazol-1-yl) Hexalin (0.13g, 91% yield).LC/MS (table 1, method w) Rt=0.210min.；MS m/z:182(M+ H)+.
Preparation #7：(trans) -3- (4- amino -1H- pyrazol-1-yl) Hexalin
Step A：3- ((tert-butyl dimetylsilyl) epoxide) Hexalin
To hexamethylene -1,3- glycol (10g, 86mmol) and imidazoles (8.9g, the 130mmol) solution in THF (300mL) Middle interpolation tert-butyl chlorodimethylsilane (5.2g, 34.4mmol).By this reactant mixture at about 15 DEG C stir about 12h.? Decompression is lower to be removed solvent and dilutes this residue with water (100mL).Extract this material with EtOAc (2x200mL), through anhydrous Na2SO4It is dried, filter and concentrate the 3- ((tert-butyl dimetylsilyl) epoxide) to provide yellow oily under reduced pressure Hexalin (7.8g, 37% yield).1H NMR (400MHz, chloroform-d) δ=4.12-3.98 (m, 1H), 3.95-3.77 (m, 1H),1.95-1.74(m,2H),1.72-1.64(m,1H),1.62-1.49(m,3H),1.48-1.40(m,1H),1.35-1.26 (m, 1H), 0.89-0.86 (m, 9H), 0.06 (d, J=3.1Hz, 3H), 0.04--0.01 (m, 3H)
Step B：(trans) -3- ((tert-butyl dimetylsilyl) epoxide) cyclohexyl) -4- nitro -1H- pyrazoles and (cis) -3- ((tert-butyl dimetylsilyl) epoxide) cyclohexyl) -4- nitro -1H- pyrazoles
At about 0 DEG C, to 4- nitro -1H- pyrazoles (3.6g, 32.2mmol), 3- ((tert- butyldimethylsilyl Base) epoxide) Hexalin (7.8g, 32.2mmol) and triphenylphosphine (12.6g, 48.2mmol) be in the solution in THF (250mL) Add solution in THF (50mL) for the DIAD (9.4mL, 48.2mmol).This reactant mixture is heated to about 15 DEG C and stirs About 12h.Remove solvent under reduced pressure and pass through with petroleum ether/EtOAc (50:1 to 30:1) silica gel chromatography of eluting carrys out purification The residue that this obtains is to provide (trans) -3- ((tert-butyl dimetylsilyl) epoxide) cyclohexyl) -4- nitro -1H- Pyrazoles (3.1g, 29% yield).1H NMR (400MHz, chloroform-d) δ=8.14 (s, 1H), 8.07 (s, 1H), 4.56 (tt, J= 3.7,11.7Hz, 1H), 4.28 (br.s., 1H), 2.13 (dd, J=1.5,10.8Hz, 2H), 1.96-1.86 (m, 2H), 1.78- 1.66 (m, 3H), 1.50-1.40 (m, 1H), 0.92 (s, 9H), 0.10-0.04 (m, 6H) and (cis) -3- ((tert-butyl diformazan Base silicyl) epoxide) cyclohexyl) -4- nitro -1H- pyrazoles (1.84g, 17% yield)1H NMR (400MHz, chloroform-d) δ =8.17 (s, 1H), 8.07 (s, 1H), 4.17 (tt, J=3.9,12.0Hz, 1H), 3.77-3.68 (m, 1H), 2.40-2.32 (m, 1H), 2.15 (d, J=12.3Hz, 1H), 1.94 (dt, J=3.5,6.6Hz, 2H), 1.80-1.70 (m, 1H), 1.60 (dq, J=3.1,12.2Hz, 1H), 1.47-1.28 (m, 2H), 0.88 (s, 9H), 0.13--0.01 (m, 6H).
Step C：(trans) -3- (4- nitro -1H- pyrazol-1-yl) Hexalin
To (trans) -3- ((tert-butyl dimetylsilyl) epoxide) cyclohexyl) -4- nitro -1H- pyrazoles (1g, 3.07mmol) add solution in MeOH (5mL) for the HI (0.513ml, 3.07mmol) in the solution in MeOH (30mL).Will This reactant mixture stir about 12h at 15 DEG C.Under reduced pressure remove solvent and by the residue obtaining saturation aqueouss NaHCO3(30mL) segmentation and EtOAc (100mL) between.The aqueouss sodium thiosulfate (2x30mL) of this organic layer saturation is washed Wash, through Na2SO4It is dried, filter and concentrate (trans) -3- (4- nitro -1H- pyrazoles -1- to provide yellow solid under reduced pressure Base) Hexalin (0.64g, 94% yield).LC/MS (table 1, method w) Rt=1.07min.；MS m/z:212(M+H)+.
Step D：(trans) -3- (4- amino -1H- pyrazol-1-yl) Hexalin
To (trans) -3- (4- nitro -1H- pyrazol-1-yl) Hexalin (0.3g, 1.42mmol) in THF (50mL) Add Raney nickel (1g, 17.04mmol) in solution.In a hydrogen atmosphere, by this reactant mixture at 15 DEG C stir about 12h. This reactant mixture is passed through kieselguhrPad filters and concentrates (anti-in light red solid to provide under reduced pressure Formula) -3- (4- amino -1H- pyrazol-1-yl) Hexalin (0.23g, 85% yield).LC/MS (table 1, method w) Rt= 0.198min.；MS m/z:182(M+H)+.
Preparation #8：(cis) -3- (4- amino -1H- pyrazol-1-yl) Hexalin
Step A：(cis) -3- (4- nitro -1H- pyrazol-1-yl) Hexalin
To (cis) -3- ((tert-butyl dimetylsilyl) epoxide) cyclohexyl) -4- nitro -1H- pyrazoles (0.9g, 2.77mmol, prepares #7, step B) add HI (0.54ml, 3.32mmol) in the solution in MeOH (30mL) in MeOH (5mL) solution in.By this reactant mixture at about 15 DEG C stir about 12h.Remove solvent residual by obtain under reduced pressure Excess is in aqueouss NaHCO of saturation3(30mL) segmentation and EtOAc (100mL) between.Aqueous sulfur generation by this organic layer saturation Sodium sulfate (2x30mL) washs, through Na2SO4It is dried, filter and concentrate under reduced pressure to provide (cis) -3- (4- nitro -1H- pyrrole Azoles -1- base) Hexalin (0.54g, 88% yield).LC/MS (table 1, method w) Rt=1.07min.；MS m/z:212(M+H)+.
Step B：(cis) -3- (4- amino -1H- pyrazol-1-yl) Hexalin
To (trans) -3- (4- nitro -1H- pyrazol-1-yl) Hexalin (0.54g, 2.56mmol) in THF (50mL) Add Raney nickel (1g, 17.04mmol) in solution.In a hydrogen atmosphere, by this reactant mixture at 15 DEG C stir about 12h. This reactant mixture is passed through kieselguhrPad filters and concentrates under reduced pressure to provide the (suitable of pinkiness solid Formula) -3- (4- amino -1H- pyrazol-1-yl) Hexalin (0.41g, 87% yield).LC/MS (table 1, method w) Rt= 0.232min.；MS m/z:182(M+H)+.
Preparation #9：Ethyl 4- (4- amino -1H- pyrazol-1-yl) naphthenic acid ester
Step A：Ethyl 4- (4- nitro -1H- pyrazol-1-yl) naphthenic acid ester
Round-bottomed flask is filled with ethyl 4- hydroxycyclohexanecarboxylate ester (4.1g, 23.8mmol), 4- nitro -1H- pyrazoles (2.2g, 19.0mmol) and the PPh in THF (95mL)3(6.2g, 23.8mmol).Add DIAD (7.4ml, Before 38.1mmol), with nitrogen to this reaction degasification about 5min.By this reactant mixture at about 60 DEG C stir about 16h.This is molten Agent concentrates under reduced pressure.By with the silica gel chromatography of EtOAc/ heptane (0-100%) eluting, this roughage is carried out purification with Ethyl 4- (4- nitro -1H- pyrazol-1-yl) naphthenic acid ester (5.0g, quantitative yield) is provided.LC/MS (table 1, method h) Rt =2.22min.；MS m/z:268(M+H)+.
Step B：Ethyl 4- (4- amino -1H- pyrazol-1-yl) naphthenic acid ester
At 50 DEG C under 10 Ba Qing, by ethyl 4- (4- nitro -1H- pyrazol-1-yl) naphthenic acid ester (5.1g, 18.9mmol) solution in EtOH (95mL) is by the H type pipe with 10%Pd/C box.This reaction solution is passed through this reaction Device circulates 5h.This solvent is concentrated under reduced pressure to provide ethyl 4- (4- amino -1H- pyrazol-1-yl) naphthenic acid ester (4.5g, quantitative yield).LC/MS (table 1, method h) Rt=1.30min.；MS m/z:238(M+H)+.
Preparation #10：Tert-butyl 4- (4- amino -1H- pyrazol-1-yl)-lupetidine -1- formic acid esters
Step A：Dimethyl 2,6- dimethyl -4- oxo-piperidine -3,5- dicarboxylic acid esters
At -30 DEG C, dimethyl 3- oxoglutarate (100g, 574mmol) and acetaldehyde (65.8g, 1.5mol) are mixed Compound ammonia gas bubbling reaches saturation until this liquid.This solution is stored about 20h in fridge.By with (PE: EtOAc=10:1 to PE:EtOAc=1:2) silica gel chromatography of eluting carries out purification to provide dimethyl 2 to yellow residue, 6- dimethyl -4- oxo-piperidine -3,5- dicarboxylic acid esters (120g, 50% yield, 60% purity).1H NMR (400MHz, chloroform- D) 3.73-3.70 (m, 9H), 3.39-3.31 (m, 2H), 3.04-2.98 (m, 2H), 1.19 (d, J=6.2Hz, 6H).
Step B：Lupetidine -4- keto hydrochloride
By dimethyl 2,6- dimethyl -4- oxo-piperidine -3,5- dicarboxylic acid esters (120g, 286mmol) are in 10% aqueouss HCl (900mL) solution in is heated to about 110 DEG C and continues 24h.By this solvent concentrate under reduced pressure be given lupetidine- 4- keto hydrochloride (50g, 80% yield), is directly used in next step.1H NMR(400MHz,DMSO-d6)10.15-9.80 (m, 2H), 3.82 (d, J=4.4Hz, 1H), 3.59-3.45 (m, 1H), 2.75-2.60 (m, 2H), 2.47-2.34 (m, 2H), 1.38-1.27(m,6H)
Step C：Tert-butyl 2,6- dimethyl -4- oxo-piperidine -1- formic acid esters
To 2,6- lupetidine -4- keto hydrochloride (50g, 281mmol) in Isosorbide-5-Nitrae-dioxane (350mL) and water (350mL) Na is added batch-wise in the solution in2CO3(59g, 562mmol).Add Boc anhydride (123g, 562mmol) and will obtain Reactant mixture at about 15 DEG C stir about 24h.This solvent is concentrated under reduced pressure.By the residue obtaining with MTBE (3 × 400mL) extract and this organic layer is washed and used anhydrous Na with saline (300mL)2SO4Washing.After evaporation, by with (PE is extremely PE:EA=10:1) silica gel column chromatography of eluting carries out purification to provide tert-butyl 2,6- dimethyl -4- oxo to crude product Piperidines -1- formic acid esters (25g, 38% yield), this product is trans/cis=2:1 mixture.
1H NMR (400MHz, chloroform-d) 4.66 (dd, J=4.9,6.8Hz, 2H), 4.32 (t, J=6.3Hz, 1H), 2.79 (dd, J=6.5,17.8Hz, 1H), 2.66 (dd, J=7.6,14.7Hz, 2H), 2.31 (dd, J=1.6,17.6Hz, 1H), 2.24-2.17 (m, 2H), 1.43 (d, J=2.3Hz, 15H), 1.23-1.17 (m, 10H).
Step D：Tert-butyl 4- hydroxyl-lupetidine -1- formic acid esters
At about 0 DEG C, to tert-butyl 2,6- dimethyl -4- oxo-piperidine -1- formic acid esters (25g, 110mmol) is in EtOH (75mL) add NaBH in the solution in4(6.24g, 165mmol).The solution obtaining is heated to about 15 DEG C and stir about 4h. Adding saturation aqueouss NH4Before Cl (80mL), this reactant mixture is cooled to about 0 DEG C.This solvent is evaporated under reduced pressure And EtOAc (100mL) is added in this residue.Extracted with EtOAc (3 × 100mL) by this two separate and by this aqueous layer Take.The organic layer that this is merged is through anhydrous Na2SO4It is dried and evaporates to provide the tert-butyl 4- hydroxyl -2,6- in colorless oil Lupetidine -1- formic acid esters (20g, 79% yield).1H NMR (400MHz, chloroform-d) 4.47-4.37 (m, 1H), 4.31- 4.13(m,2H),4.01(br.s.,1H),3.94-3.82(m,1H),2.25-2.14(m,1H),2.09-1.99(m,2H), 1.98-1.79(m,2H),1.63-1.53(m,2H),1.45(s,13H),1.39-1.28(m,6H),1.23-1.12(m,2H).
Step E：Tert-butyl 2,6- dimethyl -4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- formic acid esters
To tert-butyl 4- hydroxyl -2,6- lupetidine -1- formic acid esters (8.9g, 38.8mmol), 4- nitro -1H- pyrazoles (4.39g, 38.8mmol) and PPh3(15.3g, 58.2mmol) in the solution in THF (150ml) Deca DIAD (11.3mL, 58.2mmol).By this reactant mixture, at about 0 DEG C, stir about 10min is then heated to about 30 DEG C and stir about 16h.Should Reactant mixture segmentation between EtOAc and saline.By this organic moiety through anhydrous Na2SO4It is dried, filter and dense under reduced pressure Contracting.There is provided white solid by purification being carried out to roughage with the silica gel chromatography of EtOAc/ petroleum ether (0-10%) eluting Tert-butyl 2,6- dimethyl -4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- formic acid esters (7g, 56% yield).
1H NMR (400MHz, chloroform-d)=8.19 (s, 1H), 8.10 (d, J=1.6Hz, 1H), 4.77-4.46 (m, 3H), 3.89-3.76 (m, 1H), 2.43-2.24 (m, 1H), 2.16-1.90 (m, 4H), 1.49 (d, J=1.6Hz, 11H), 1.46 (d, J=6.7Hz, 2H), 1.38-1.27 (m, 6H)
Step F：Tert-butyl 4- (4- amino -1H- pyrazol-1-yl)-lupetidine -1- formic acid esters
To tert-butyl 2,6- dimethyl -4- (4- nitro -1H- pyrazol-1-yl) piperidines -1- formic acid esters (2g, 6.17mmol) In THF (50mL) and NH4Add Raney nickel (1.1g, 18.1mmol) in solution in OH (0.5mL).In a hydrogen atmosphere, will This reactant mixture is stirred at room temperature about 2h.By this reactant mixture through kieselguhrPad filters and in decompression Lower concentration with provide tert-butyl 4- (4- amino -1H- pyrazol-1-yl) -2,6- lupetidine -1- formic acid esters (1.8g, 99% Yield).LC/MS (table 1, method w) Rt=0.96min.；MS m/z:295(M+H)+.
General program A：Aryl or the nucleophilic displacement of fluorine of hetaryl halogenides and amine
Add aryl or hetaryl halogenides (preferably 1 equivalent), amine or amine in microwave tank, bottle or round-bottomed flask Salt (1-10 equivalent, preferably 1.1-2 equivalent), solvent (such as Isosorbide-5-Nitrae-dioxane, MeCN, i-PrOH, n-PrOH, n-BuOH, first Benzene, DMSO, DMF, DMA or EtOH, preferably Isosorbide-5-Nitrae-dioxane [microwave] or i-PrOH [heating power heating]) and alkali is (for example K2CO3、Na2CO3, TEA or DIEA, preferably TEA, DIEA or K2CO3, 1-5 equivalent, preferably 2-4 equivalent).Optionally this virtue Base or hetaryl halogenides and amine or amine salt is every kind of before the combination individually dissolves in a solvent.By this reactant mixture about Under 40 DEG C -220 DEG C (preferably about 80 DEG C -100 DEG C) heating power heating about 0.5-36h (preferably about 8-24h) or about 100 DEG C - Stand microwave heating about 0.5-8h (preferably about 0.5-2h) under 200 DEG C (preferably about 130 DEG C -150 DEG C).In this reaction as led to Cross that TLC, LC/MS or HPLC monitored be not fully finished in the case of, by optional interpolation more polyamines or amine salt (1-10 Equivalent, preferably 0.5-1.5 equivalent) and/or alkali (such as K2CO3、Na2CO3, TEA or DIEA, preferably TEA, DIEA or K2CO3, 1-5 equivalent, preferably 2-4 equivalent), this reaction can weigh under about 40 DEG C -220 DEG C (preferably about 80 DEG C -100 DEG C) Fresh warp thread is subject to heating power heating about 0.5-8h (preferably about 1-2h) or under about 120 DEG C -200 DEG C (preferably about 130 DEG C -150 DEG C) Again stand microwave heating and continue other about 1-8h (preferably about 0.5-2h).Repeat this process until reacting not further Carry out.After being cooled to ambient temperature, process this reaction using one of following method：Method 1：This reaction is concentrated under reduced pressure. Method 2：When optionally with one or more machine solvent such as Et2When O, DCM and/or petroleum ether, the anti-of precipitation will be comprised Mixture is answered to filter to collect target compound.Method 3：This reactant mixture is diluted with organic solvent such as MeOH, adds Silica gel, and by this mixture concentrate under reduced pressure with the chromatography of standby solids laden carry out separate.Method 4：Organic adding Before solvent such as EtOAc or DCM, this reactant mixture is concentrated under reduced pressure, and and then optionally use water and/or saline Washing, via anhydrous Na2SO4Or MgSO4It is dried, filter or be decanted, and concentrate under reduced pressure.Method 5：To organic solvent for example These layers are simultaneously separated by optional interpolation water in EtOAc or DCM or saline.Then with other organic solvent such as EtOAc or DCM optionally extracts this aqueous layer.Optionally wash the organic layer of these merging with saline or water, through anhydrous MgSO4Or Na2SO4 It is dried, filter or be decanted, and concentrate under reduced pressure.
The explanation of general program A
Preparation #A.1：8- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one
To 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine (0.200g, 0.720mmol, Noah's ark drugmaker) and 8- Amino -4,5- dihydro -1H- benzo [b]-azatropylidene -2 (3H) -one (0.139g, 0.792mmol, Ai Site company) is in i-PrOH (8mL) add DIEA (0.377mL, 2.16mmol) in the solution in.This mixture is heated to the about 24h that flows back.By obtain Solution is cooled to room temperature and filters to provide 8- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia in brown solid Base) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one (0.15g, 56%)：1H NMR(DMSO-d6)δ9.62(s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 7.61-7.67 (m, 2H), 7.23 (d, J=8.4Hz, 1H), 2.65 (t, J= 6.4Hz,2H),2.07-2.15(m,3H),1.23(m,1H).
Table A .1 is as [real from 8- bromo- 6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine described in general program A Example #11, step E] example prepared.
General program B：Aryl or hetaryl halogenides are reacted with the Buchwald-Hartwig of amine
By aryl or hetaryl halogenides (1.0 equivalent), amine (1 to 2.2 equivalent), preferably 1 to 1.2 equivalent), palladium chtalyst Agent (such as Pd2dba3、Pd(OAc)2, preferably Pd (OAc)2；0.01 to 1.0 equivalent, preferably 0.04 to 0.1 equivalent), part (such as Xphos, Xantphos or tert-butyl-X-phos, preferably Xantphos or XPhos, 0.01 to 2.0 equivalent, preferably Ground 0.04 to 0.1 equivalent) and alkali (such as K2CO3、Na2CO3、Cs2CO3、K3PO4, NaOt-Bu, KOt-Bu, KOAc, KOH, preferably Ground Cs2CO3Or K2CO3；1 to 5 equivalent, preferably 1 to 3 equivalent) mixture add to solvent (such as Isosorbide-5-Nitrae-dioxane, t- BuOH, preferably t-BuOH) in.The degasification about 80 under inert atmosphere (such as nitrogen or argon, preferably nitrogen) by this mixture DEG C under 150 DEG C (preferably about 85 DEG C to 95 DEG C) with conventional or microwave heating method heating about 2 to 24h (preferably about 16h).This mixture is cooled to room temperature.By this mixture optionally by medium (such as silica gel or kieselguhr) Filter, this filtration is with suitable solvent (such as EtOAc, Isosorbide-5-Nitrae-dioxane, THF, MeCN, DCM, Et2O、MeOH、EtOH、 DMSO、1:1MeOH/DMSO or 2:1MeOH/DMSO, preferably MeOH/DMSO) rinse and and then this filtrate optionally exists Decompression is lower or concentrates to provide residue under flow of warm nitrogen gas.
The explanation of general program B
Preparation #B.1：The chloro- N- of 6- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine
Add the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine (0.70g, 3.0mmol, example # in microwave vial 1, step A), 1- methyl isophthalic acid H- pyrazoles -3- amine (0.32g, 3.3mmol, matrix scientific ＆ technical corporation (Matrix Scientific)), Xantphos (0.37g, 0.63mmol), Pd (OAc)2(0.068g, 0.30mmol), cesium carbonate (2.453g, 7.53mmol) and 1,4- dioxane (7mL).Then at about 120 DEG C, this mixture is heated about 1.5h in microwave.Will be cold for this reactant mixture But to room temperature, filter, washed with DCM and MeOH.Silica gel (2g) is added to filtrate.This mixture is concentrated simultaneously under reduced pressure By the 0-50%DCM/MeOH/NH in DCM4OH(90:9:1) silica gel chromatography of eluting carries out purification.Merging comprises The fraction of product and under reduced pressure concentrate and under the vacuum at about 55 DEG C be dried be given the chloro- N- of 6- (1- methyl isophthalic acid H- pyrazoles- 3- yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine (0.55g, 73%, 75% purity being obtained by NMR)：LC/MS (table 1, method a) Rt=1.29min.；MS m/z:249(M+H)+.
General program C：Aryl or hetaryl halogenides and boric acid or boratory reaction
To aryl halide (preferably 1 equivalent), boric acid or borate (1-2.5 equivalent, preferably 1.3-2.0 equivalent), With inorganic base (for example, potassium fluoride, sodium carbonate or cesium carbonate, preferably cesium carbonate；1.1-16 equivalent, preferably 2-3 equivalent) Solvent (such as THF, DME, DMF, 1,4- dioxane, DME/ water, 1,4- dioxane/water, toluene/EtOH/ water, THF/MeOH/ water Or 1,4- dioxane/EtOH/ water；Preferably THF/MeOH/ water, 1,4- dioxane/EtOH/ water or DME) in mixture in add Plus palladium catalyst (such as three (benzylideneacetone) two palladium (0), tetrakis triphenylphosphine palladium (0), double (acetic acid)-triphenylphosphine palladium (II), Polymer binding FibreCatTM1032nd, SiliaCat DPP-Pd [Silicycle], (1,1 '-bis- (diphenyl-phosphino) two cyclopentadienyl Ferrum) double (triphenyl-phosphine) palladium (II) of dichloro palladium (II) or dichloro；Preferably three (benzylideneacetone) di-palladium (0) or four-(triphen Base phosphine) palladium (0), 0.01-0.20 equivalent, preferably 0.1 equivalent) and optionally add part (for example tricyclohexyl phosphine, XPhos, Xantphos, tert-butyl-XPhos or three-tert-butyl-phosphate；Preferably no part, XPhos or Xantphos； 0.01-1.0 equivalent, preferably 0.1-0.2 equivalent).By this reactant mixture in microwave at about 40 DEG C -120 DEG C (preferably about 80 DEG C -90 DEG C) heating power heating about 1-24h (preferably about 2h), or at about 100 DEG C -200 DEG C (preferably about 120 DEG C -150 DEG C) Heating power heating about 5min-3h (preferably about 30min).As incomplete in monitored by TLC, HPLC or LCMS in this reaction In the case of completing, optionally add other reagent and reactant and this reaction is stood in microwave more heating and continuous in addition About 5min-3h (preferably about 30min) or at a temperature of same or higher by identical or different heating means heating power Heating 1-24h (preferably about 2h).Repeat this process until reaction be not further carried out.This reactant mixture is allowed to be cooled to Ambient temperature is simultaneously processed one of using the following method.Method 1., for the reaction comprising water, can mix to this reaction Thing optionally filters, and then uses organic solvent (such as DCM or EtOAc) to dilute.Separate these layers, by this organic solution optionally With water and/or salt water washing, through MgSO4Or Na2SO4It is dried, filters, and remove solvent under reduced pressure.This reaction is mixed by method 2. Compound concentrates under reduced pressure.Method 3. is passed through to filter this catalyst of removal and is concentrated this filtrate under reduced pressure or use this filtrate Water and/or salt water washing, separate these layers, by this organic solution through MgSO4Or Na2SO4It is dried, filter, and remove under reduced pressure Solvent.Method 4. is added water and/or MeOH and the precipitation that obtain is collected by filtration.
The explanation of general program C
Preparation #C.1：Tert-butyl 3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) ammonia Base)-[1,2,4] triazole [1,5-a] pyrazine -6- base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters
To 8- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- benzo [b] azepine Tall and erect -2 (3H) -one (0.500g, 1.34mmol prepare #A.1) add in the solution in DME (12mL) tert-butyl 3- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (0.791g, 2.68mmol, Kang Beibo Ces Co., Ltd), XPhos (0.058mg, 0.134mmol), three (benzylideneacetone) di-palladium (0) (0.123g, 0.134mmol) and Cs2CO3(1.30g, 4.02mmol).By this mixture in microwave reactor at about 140 DEG C Heating about 30min.The solution obtaining is filtered and by this solid washed with DCM, then uses water and salt water washing.By this organic facies Through Na2SO4It is dried and concentrated to provide thick solid, this thick solid is washed to provide tert-butyl 3- in brown solid with MeOH (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] triazole [1,5-a] pyrazine - 6- yl) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (0.25g, 40%)：1H NMR(DMSO-d6)δ10.05(s,1H),9.65 (d, J=7.9Hz, 1H), 8.60 (s, 1H), 8.50-8.38 (m, 1H), 7.82 (d, J=12.3Hz, 1H), 7.71 (t, J= 9.5Hz, 1H), 7.20 (t, J=6.6Hz, 1H), 6.68 (d, J=11.9Hz, 1H), 4.44 (br s, 2H), 4.24 (br s, 2H),2.64(br s,2H),2.24-1.96(m,4H),1.59-1.35(s,9H).
C.1, table uses general program C from the bromo- N- of 6- (4- morphlinophenyl)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (being prepared from 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine [Noah's ark drugmaker] and 4- morpholine aniline using B) preparation Example
General program D：The acid cleavage of the amine protected by Boc-
To N-Boc amine (1 equivalent) organic solvent (such as DCM, DCE, EtOAc, Isosorbide-5-Nitrae-dioxane or MeOH, preferably DCM, EtOAc, MeOH or 1,4- dioxane) in solution in add acid (such as TFA or HCl (and HCl be can commercially available or use MeOH and chloroacetic chloride in-situ preparation), preferably HCl；2 to 100 equivalents, preferably 25 to 50 equivalents).By this mixture about 0 DEG C to stir about 1 under 100 DEG C (preferably about 20 DEG C to 60 DEG C) to 24h (preferably about 1 to 12h).It is optionally possible to add another Outer acid (2 to 35 equivalents, preferably 20 to 25 equivalents) and by this mixture at about 0 to 100 DEG C (preferably about 20 DEG C to 60 DEG C) under stir about 1 to 24h (preferably about 1 to 6h).If solid occurs in mixture, can be by this mixture optionally mistake Filter by this solid organic solvent such as 1,4- dioxane or Et2O washs.Then by the solid obtaining optionally under reduced pressure It is dried to provide target compound.Alternately, this mixture optionally can be concentrated under vacuo to provide final chemical combination Thing.Alternately, can optionally by this residue or this solution in water and organic solvent (such as EtOAc, Et2O or DCM) it Between segmentation.Separate this organic layer can be optionally with no particular order water and/or comprise alkali (such as NaHCO3、Na2CO3、 NaOH, KOH or NH4OH aqueous solution) and/or comprise inorganic salt (such as NaCl, Na2SO3Or Na2S2O3) aqueous solution enter Row washing.Then this organic solution optionally can be used desiccant (for example anhydrous MgSO4Or Na2SO4) be dried, filter and Reduced under vacuum is to provide target compound.
The explanation of general program D
Preparation #D.1：8- ((6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- two Hydrogen -1H- benzo [b] azatropylidene -2 (3H) -one
To 3- [8- (2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base amino)-[1,2,4] triazole [1, 5-a] pyrazine -6- base]-pyrrolidine -1- carboxylic acid methylamide (1.60g, 3.45mmol, prepare #E.1) is in EtOAc (20mL) Solution in add HCl/EtOAc (20mL).By this mixture at about 25 DEG C stir about 12h.By the solution obtaining in decompression Lower concentration is to provide 8- ((6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia in brown solid Base) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one (1.20g, 96%)：LC/MS (table 1, method d) Rt= 2.12min；MS m/z:364(M+H)+.
The table D.1 example as prepared using HCl described in general program D
General program E：The hydrogenation of double bond
Reactor is filled with alkene (1 equivalent), can be pure or as organic solvent or solvent (such as THF, EtOAc, MeOH, EtOH or MeOH/AcOH, preferably THF or MeOH) solution in mixture, subsequently adds Pd (OH)2Or Pd/C (0.005-3 equivalent, preferably 2 equivalents), in solid form or organic solvent or solvent (such as AcOH, THF, EtOAc, MeOH, EtOH or MeOH/AcOH, preferably AcOH) in mixture.Optionally this alkene is added to Pd mixture In.This reactant mixture is carried out bubbling with hydrogen.Under hydrogen, about reach 60psi (preferably about 50psi) in atmospheric pressure, about Under 20 DEG C -60 DEG C (preferably ambient temperatures), the stirring of this mixture or shake (are stirred preferably when using atmospheric hydrogen or worked as Using higher pressure hydrogen when shake) about 0.5-5 days (preferably about 1-3 days).This reactant mixture is passed through kieselguhrPad or nylon membrane filtration.By this filter cake with organic solvent (such as THF, EtOAc, DCM, MeOH or EtOH, preferably This reaction dissolvent of ground) rinse and concentrate this filtrate to provide target compound under reduced pressure.
Selected with identical solution listed above, using H type pipe, this reaction also can be entered with fluid chemistry style form OK.Under about 20 DEG C -80 DEG C (preferably 30 DEG C -60 DEG C), under the hydrogen from 1 bar to 80 bars (preferably about 40-60 bar), will be in The reactant mixture of solution passes through with Pd (OH)2The Ka Sekate of/C or Pd/C fillingLast about 0.5-24h (excellent Selection of land about 8h).Then this mixture is concentrated under reduced pressure to provide target compound.
The explanation of general program E
Preparation #E.1：Tert-butyl 3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) ammonia Base)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters
To 3- [8- (2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base amino)-[1,2,4] triazole [1, 5-a] pyrazine -6- base] -2,5- dihydro-pyrrole -1- carboxylic acid tert-butyl ester (2.0g, 4.33mmol, prepare #C.1) is in MeOH (300mL) add 10%Pd/C (2g) and AcOH (30mL) in the solution and in THF (60mL).In H2(50psi) under atmosphere, At about 25 DEG C, by this suspension stir about 72h.The solution obtaining is passed through kieselguhrFilter and dense under reduced pressure Contracting is to provide tert-butyl 3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] Triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters (1.8g, 90%)：LC/MS (table 1, method c) Rt=1.40min； MS m/z:464(M+H)+.
Table is E.1 as use Pd/C or Pd (OH) described in general program E2The example of/C preparation
General program F：Form amide from acid chloride and amine or from chloro-formate and amine formation carbamate
Under 0 DEG C to 25 DEG C (preferably room temperature), optionally as hydrochlorate, to organic solvent (such as DCM, DCE, DMF、DMA、NMP、THF、Et2O or Isosorbide-5-Nitrae-dioxane, preferably DMA, DMF or DCM) in amine (1 equivalent) solution in add alkali (such as TEA, DIEA or pyridine；1 to 50 equivalent, preferably pyridine 10 to 30 equivalent or DIEA 2 to 3 equivalent) and acid chloride or Chloro-formate (1 to 3 equivalent, preferably 1.2 equivalents).Allow this mixture at about 0 DEG C to 60 DEG C (preferably about 25 DEG C to 50 DEG C) under stir about 5min to 20h (preferably about 1 to 12h).This mixture is optionally neutralized with AcOH.This mixture is appointed Selection of land concentrates in a vacuum to provide final compound.By this mixture optionally by medium (such as silica gel or kieselguhr) filter, this filtration is with suitable solvent (such as EtOAc, Isosorbide-5-Nitrae-dioxane, THF, MeCN, DCM, Et2O、 MeOH, EtOH) rinse and and then by this filtrate optionally under reduced pressure or concentrate to provide residue under flow of warm nitrogen gas.Can With optionally by this residue or this solution in water and organic solvent (such as EtOAc, Et2O or DCM) between segmentation.Separating should Organic layer simultaneously can be optionally with no particular order water and/or comprise sour (such as HCl, AcOH or NH4Cl aqueous solution) And/or comprise alkali (such as NaHCO3、Na2CO3, NaOH, KOH or NH4OH aqueous solution) and/or comprise inorganic salt (for example NaCl、Na2SO3Or Na2S2O3) aqueous solution washed.Then this organic solution optionally can be used desiccant (for example Anhydrous MgSO4Or Na2SO4) be dried, filter and be concentrated under vacuum to provide target compound.
The explanation of general program F
Example #F.1：8- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia Base) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one
To 8- ((6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- Benzo [b] azatropylidene -2 (3H) -one (0.090g, 0.25mmol prepare #D.1) adds DIEA in the solution in DCM (4mL) (0.130mL, 0.743mmol), subsequently adds acryloyl chloride (0.045g, 0.495mmol).This mixture is stirred at about 25 DEG C Mix about 12h.The solution obtaining is concentrated under reduced pressure to provide crude product, this crude product is passed through preparative-HPLC (table 1, side Method i) purification is to provide 8- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine-of white solid 8- yl) amino) -4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one (0.054g, 52%).LC/MS (table 1, method d) Rt =2.62min；MS m/z:418(M+H)+.BTK enzyme IC50=A.
Table is F.1 as the example of the use acid chloride preparation described in general program F
General program G：The chiral preparative HPLC of stereoisomer separates
The racemic mixture of compound is stood chirally purified using preparation HPLC.In table 2, method (1-6) Describe the representative gradient using mobile phase A and B.When pointing out, the chiral separation for racemic mixture is respectively adopted Method (1-6) from table 2.
The explanation of general program G
Preparation #G.1 and #G.2：(S)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] three Azoles [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters and (R)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) ammonia Base)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters
By chiral preparative (table 2, method 6) separate tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino) - [1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters (example #6, step C) racemic mixture to be given (S)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrroles Alkane -1- formic acid esters (0.435g, 40.2%, OR=bears) and (R)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) ammonia Base)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters (0.442g, 40.9%, OR=just) [three-dimensional Be any distribution]：LC/MS (table 1, method l) Rt=1.96min.；MS m/z:385(M+H)+.
G.1, the example that table is prepared using chiral SFC (table 2, method 17 or 18) from general program G
General program H：Form sulfonamide from sulfonic acid chloride and amine
At about 0 DEG C, to amine (preferably 1 equivalent) and alkali (such as pyridine, DIEA or TEA；1.1-5 equivalent, preferably 2- 3 equivalent DIEA) add yellow acyl sulfonic acid chloride in the solution in organic solvent (for example, DMA, DMF or THF, preferably DMA) (1.0-1.2 equivalent).After about 5-120min (preferably 10-30min), this reactant mixture is lentamente stirred and is added to ice In water.After melting completely as fruit ice, precipitation occurs, be collected by vacuum filtration the solid obtaining to provide crude product.Alternative Ground, can carry out extraction processing under reduced pressure or concentrate to this reactant mixture.
The explanation of general program H
Example #H.1：(S)-N- (3,4- Dimethoxyphenyl) -6- (1- (ethenesulfonyl) pyrrolidin-3-yl)-[1,2, 4] triazole [1,5-a] pyrazine -8- amine
At about 0 DEG C, to (S)-N- (3,4- Dimethoxyphenyl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5- A] pyrazine -8- amine (0.073g, 0.21mmol, example #3, step B) and DIEA (0.093mL, 0.54mmol) be at DMA (1.5mL) In solution in add ethenesulfonyl chloride (0.025mL, 0.22mmol).After about 20min, this reactant mixture is lentamente stirred And be added in frozen water (about 10mL).After this ice melts completely, be collected by vacuum filtration the solid obtaining and at 55 DEG C It is dried to provide impure product under vacuum.This solid is ground with MeOH (1mL).It is collected by vacuum filtration the solid obtaining Washed with other MeOH (1mL) simultaneously and be dried in a vacuum at 55 DEG C, to provide by LCMS, there is little purity change Solid.This filtrate and solid are reconsolidated, concentrates under reduced pressure and the silicon by the 0-5%MeOH eluting in DCM Glue chromatography carries out purification.The fraction comprising product is concentrated under reduced pressure and is dried in a vacuum at about 55 DEG C and to be given be in (S)-N- (3,4- Dimethoxyphenyl) -6- (1- (ethenesulfonyl) pyrrolidin-3-yl)-[1,2,4] triazole of white solid [1,5-a] pyrazine -8- amine (0.024g, 26%)：LC/MS (table 1, method e) Rt=2.00min.；MS m/z:431(M+H)+. BTK enzyme IC50=A
General program I：Form cyanamide from amine with Bromine cyanide.
Under about -5 DEG C to 25 DEG C (preferably 0 DEG C), to amine (preferably 1 equivalent) and alkali (such as cesium carbonate or TEA；1- 10 equivalents, preferably 1-5 equivalent) add in the mixture in solvent such as DCM, DMA, THF or DMF (preferably DMA or THF) Plus Bromine cyanide. (1-3 equivalent, preferably 1.1-2.2 equivalent).Maintain this reaction temperature or allow its heating.After about 5-120min, This reactant mixture water (10mL) is diluted and extracts (for example using DCM).This organic layer merging optionally is washed with salt Wash, through Na2SO4Or MgSO4It is dried, filter, and concentrate under reduced pressure.
The explanation of general program I
Example #I.1：3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) pyrrolidine -1- formonitrile HCN
At about 0 DEG C, to N- (1- methyl isophthalic acid H- pyrazole-3-yl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5- A] pyridine -8- amine (0.10g, 0.35mmol) and cesium carbonate (0.460g, 1.41mmol) be in the mixture in DMA (3.0mL) Add Bromine cyanide. (0.075g, 0.71mmol).This reactive bath technique is allowed to be heated to about 10 DEG C.After about 30min, with water (10mL) dilution And extracted with DCM (3x15mL).This organic layer merging is washed with saline (15mL), through MgSO4It is dried, filter, and subtracting Pressure concentrates.At about 55 DEG C, after being dried under vacuum, by the 0-50%DCM/MeOH/NH in DCM4OH(90:9: 1) silica gel chromatography of eluting, this residue is dissolved in DCM and is used for purification, to provide the 3- (8- in light yellow solid ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine -1- formonitrile HCN (0.076g, 70%) LC/MS (table 1, method e) Rt=1.43min.；MS m/z:309(M+H)+.BTK enzyme IC50=B
The example that Table I .1 is prepared from Bromine cyanide. using general program I
Example #1.1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone
Step A：The bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine
To the bromo- 5- chloropyridine of 2- amino -3- (10.0g, 48.2mmol, Noah's ark drugmaker) in DMF (20mL) in the solution in add DMF-DMA (17.2g, 145mmol) and by this solution at 130 DEG C stir about 18h.This is mixed Compound cools down and is evaporated to drying.Ice-cold to the brown solid in MeOH (80.0mL) and pyridine (7.80mL, 96mmol) But add hydroxylamine-o- sulfonic acid (7.63g, 67.5mmol) in the solution being stirred.This reaction is allowed to be heated to about 25 DEG C and stir about 18h.It is dissolved in DCM (150mL) and the carbon with saturation by the evaporation of this mixture and by this solid residue Sour hydrogen sodium (200mL), water (200mL) and saline (200mL) washing.This organic mixture is passed through Biotage phase separator mistake Filter is to remove the water of remnants and to be evaporated to be dried to provide the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyrrole in orange solids Pyridine, this product need not carry out other purification and can be used for next step.(6.1g, 64% is thick)：1H NMR(CDCl3)δ8.65 (d, J=1.8Hz, 1H), 8.39 (s, 1H), 7.80 (d, J=1.7Hz, 1H).
Step B.6- chloro- N- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine
Add the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine (1.59g, 6.84mmol, example # in microwave vial 1, step A), 1- methyl isophthalic acid H- pyrazoles -3- amine (0.731g, 7.52mmol, matrix scientific company (MatrixScientific)), Xantphos (0.831g, 1.44mmol), acid chloride (II) (0.154g, 0.684mmol), cesium carbonate (5.57g, 17.1mmol) With 1,4- dioxane (12mL).Then at about 120 DEG C, this mixture is heated about 1.5h in microwave.This reaction is cooled to Room temperature simultaneously concentrates under reduced pressure.This residue is carried out supersound process to provide homogeneous suspension together with MeOH (10mL), connects And filtered.All there are not pure products in LC/MS instruction in solid and filtrate.This solid and filtrate are merged, is subtracting Pressure concentrates, and is redissolved in DCM/MeOH (3:1；In 250mL), then add silica gel.This suspension is concentrated under reduced pressure, By the 0-60%DCM/MeOH/NH in DCM4OH(90:9:1) silica gel chromatography of eluting carries out purification.Merging comprises The fraction of product simultaneously concentrates under reduced pressure to provide the chloro- N- of 6- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] Pyridine -8- amine (1.63g, about 96%, about 86% purity being obtained by NMR)：LC/MS (table 1, method e) Rt=2.33min.； MS m/z:248(M+H)+.
Step C. tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine- 6- yl) -2,5- dihydro -1H- pyrroles's -1- formic acid esters
Add the chloro- N- of 6- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyrrole in 10mL microwave tube Pyridine -8- amine (0.21g, 0.84mmol), tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) - 2,5- dihydros -1H- pyrroles's -1- formic acid esters (0.35g, 1.2mmol, Kang Beibo Ces Co., Ltd), THF (5mL), MeOH (1mL) and Sodium carbonate (1.27mL, 2.53mmol).This mixture is carried out bubbling with nitrogen, then adds double (diphenylphosphino) two of 1,1'- Luxuriant ferrum-dichloro palladium (II) chloride dichloromethane complex (0.069g, 0.084mmol).This bottle is sealed.At about 130 DEG C This mixture is heated about 1h in microwave.This reactant mixture is passed through kieselguhrFilter, with DCM and MeOH Washing.Concentrate filtrate under reduced pressure.By the 0-80%DCM/MeOH/NH in DCM4OH(90:9:1) the silica gel color of eluting Spectrometry carries out purification to this crude product.Merge the fraction comprising product, concentrate under reduced pressure, be ground with MeOH (1mL).Will The solid obtaining is collected by vacuum filtration, and is washed with other MeOH (5mL) and and then does under vacuo at about 55 DEG C Dry be given tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) - 2,5- dihydros -1H- pyrroles's -1- formic acid esters (0.17g, 53%)：LC/MS (table 1, method e) Rt=3.09min.；MS m/z:382 (M+H)+.
Step D. tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine- 6- yl) pyrrolidine -1- formic acid esters
By tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (1.40g, 3.67mmol), MeOH (100mL), THF (5mL), AcOH (5mL) Add in the 10%Pd/C (0.450g, 0.423mmol) of the drying in 250mL stainless steel pressure bottle.H with 30psi2, This reactant mixture is stirred at room temperature about 16h.Analytical HPLC indicates the appearance of parent material and product.Add drying 10%Pd/C (0.450g, 0.423mmol) simultaneously continues hydrogenation about 4 days at room temperature.This mixture was carried out by nylon membrane Filter simultaneously concentrates under reduced pressure.By the 0-50%DCM/MeOH/NH in DCM4OH(90:9:1) silica gel chromatography of eluting Purification is carried out to this residue.Merge comprise product fraction and under reduced pressure concentrate and be dried under vacuum at about 55 DEG C with Provide tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrroles Alkane -1- formic acid esters (0.752g, 52%)：LC/MS (table 1, method e) Rt=2.21min.；MS m/z:384(M+H)+.
Step E.N- (1- methyl isophthalic acid H- pyrazole-3-yl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyridine - 8- amine
To tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) pyrrolidine -1- formic acid esters (0.076g, 0.20mmol) adds HCl in the solution in MeOH (0.75mL) (4M is in Isosorbide-5-Nitrae-two In alkane, 0.75mL, 3.00mmol).This reaction is stirred at room temperature about 3.5h and and then concentrates under reduced pressure.By with 0-100%DCM/MeOH/NH in DCM4OH(90:9:1) silica gel chromatography of eluting carries out purification to this residue.Merge The fraction that comprises product and concentrate under reduced pressure and be dried under vacuum at about 55 DEG C be given N- (1- methyl isophthalic acid H- pyrazoles- 3- yl) and -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine (0.061g, about 109%, about 91%, pass through NMR obtains), it need not carry out other purification and can be used for next step：LC/MS (table 1, method e) Rt=0.63min.；MS m/z:284(M+H)+.
Step F.1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone
At about 0 DEG C, to N- (1- methyl isophthalic acid H- pyrazole-3-yl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5- A] pyridine -8- amine (0.143g, 0.505mmol) and N- ethyl-N-iospropyl propyl- 2- amine (0.220mL, 1.26mmol) be in DMA (2.5mL) add acryloyl chloride (0.043mL, 0.530mmol) in the solution in.After about 2min, remove this ice bath and allow this Reaction is stirred at room temperature.After about 25min, add this reactant mixture, with water (10mL) dilution, carried out with DCM (3x10mL) Extraction.By this organic layer merging salt water washing, through MgSO4It is dried, filter, and concentrate under reduced pressure.By in DCM The silica gel chromatography of the 50%-100%EtOAc eluting maintaining 100%EtOAc for a long time purification is carried out to this crude product. Merge the fraction comprising product, and concentrate under reduced pressure, and be dried under vacuum to provide white foam at about 55 DEG C 1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidin-1-yl) Propyl- 2- alkene -1- ketone (0.11g, 65%)：LC/MS (table 1, method e) Rt=1.56min.；MS m/z:338(M+H)+.BTK enzyme IC50=A
Example #2：1- (3- (8- (6- methoxyl group pyridazine -3- base amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrole Cough up alkane -1- base) propyl- 2- alkene -1- ketone trifluoroacetate
Step A：The chloro- N- of 6- (6- methoxyl group pyridazine -3- base)-[1,2,4] triazole [1,5-a] pyridine -8- amine
Add the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine (1.00g, 4.30mmol, example # in microwave tubule 1, step A), 6- methoxyl group pyridazine -3- amine (0.538g, 4.30mmol), Xantphos (0.523g, 0.903mmol), Pd (OAc)2(0.097g, 0.43mmol), cesium carbonate (2.80g, 8.60mmol) and Isosorbide-5-Nitrae-dioxane (15mL).By this reaction with very Empty degasification simultaneously backfills nitrogen.By the sealing of this vessel and heat about 1.5h at about 120 DEG C in microwave oven.Will be cold for this mixture But, by kieselguhrFilter and concentrated.It is 20%-70%EtOAc eluting by the gradient in ethane Silica gel chromatography the residue obtaining is carried out with purification to provide the chloro- N- of 6- (6- methoxyl group pyridazine -3- base)-[1,2,4] three Azoles [1,5-a] pyridine -8- amine (0.500g, 42%)；1H NMR(CDCl3) δ 8.84 (d, J=1.7Hz, 1H), 8.30-8.20 (m, 2H), 7.65 (s, 1H), 7.09 (t, J=6.8Hz, 1H), 7.00 (dd, J=12.4,6.7Hz, 1H), 4.12 (d, J=7.1Hz, 3H).
Step B：Tert-butyl 3- (8- (6- methoxyl group pyridazine -3- base amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters
Under nitrogen, to the chloro- N- of 6- (6- methoxyl group pyridazine -3- base)-[1,2,4] triazole [1,5-a] pyridine -8- amine (3.45g, 12.47mmol), tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) -2,5- bis- Hydrogen -1H- pyrroles's -1- formic acid esters (5.52g, 18.7mmol, Kang Beibo Ces Co., Ltd), potassium carbonate (3.45g, 24.9mmol) Isosorbide-5-Nitrae - Add Pd in the mixture of dioxane (100mL) and water (50mL)2(dba)3(1.14g, 1.25mmol) and dicyclohexyl (2', 4', 6'- triisopropyl-[1,1'- diphenyl] -2- base) phosphine (0.594g, 1.25mmol).At about 100 DEG C under nitrogen, should Mixture heats about 16h.The segmentation between water and DCM by this reactant mixture.This organic layer is concentrated and is passed through to be used in Gradient in ethane is that the silica gel chromatography of 20%-80%EtOAc eluting carries out purification to provide the tert-butyl of white solid 3- (8- ((6- methoxyl group pyridazine -3- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) -2,5- dihydro -1H- pyrroles - 1- formic acid esters (3.2g, 62%).LC/MS (table 1, method d) Rt=1.38min；MS m/z:410(M+H)+.
Step C：Tert-butyl 3- (8- (6- methoxyl group pyridazine -3- base amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) pyrrolidine -1- formic acid esters
To tert-butyl 3- (8- (6- methoxyl group pyridazine -3- base amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) -2, 5- dihydro -1H- pyrroles's -1- formic acid esters (0.20g, 0.49mmol) adds 10%Pd/C in the solution in THF (120mL) (0.50g, 0.47mmol).At room temperature, in the H of about 25psi2Under, by this mixture stir about 24h.Filter this mixture simultaneously Concentrate under reduced pressure to provide tert-butyl 3- (8- ((6- methoxyl group pyridazine -3- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Pyridine -6- base) pyrrolidine -1- formic acid esters (0.18g, 90%).LC/MS (table 1, method d) Rt=1.01min；MS m/z:412(M+ H)+.
Step D：N- (6- methoxyl group pyridazine -3- base) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- Amine
To tert-butyl 3- (8- ((6- methoxyl group pyridazine -3- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Pyrrolidine -1- formic acid esters (0.600g, 1.46mmol) adds TFA (12mL, 156mmol) in the solution in DCM (360mL). This mixture is stirred at room temperature about 6h.Concentrate this mixture be given N- (6- methoxyl group pyridazine -3- base) -6- (pyrrolidine - 3- yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine, it need not carry out other purification and can be used for next step. (0.50g, 100% semifinished product)；LC/MS (table 1, method d) Rt=1.46min；MS m/z:312(M+H)+.
Step E：1- (3- (8- (6- methoxyl group pyridazine -3- base amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrole Cough up alkane -1- base) propyl- 2- alkene -1- ketone trifluoroacetate
At about 0 DEG C, to N- (6- methoxyl group pyridazine -3- base) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] Pyridine -8- amine (0.080g, 0.26mmol) and TEA (0.143mL, 1.03mmol) add propylene in the solution in DCM (2mL) Acyl chlorides (0.023g, 0.257mmol).This mixture is stirred at room temperature overnight.Add water so that this reaction is quenched.This is reacted Mixture segmentation between water and DCM.Concentrate this organic layer and (table 1, method z) carries out purification to give by preparative-HPLC Go out 1- (3- (8- (6- methoxyl group pyridazine -3- base amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone trifluoroacetate.(0.049g, 52%)；LC/MS (table 1, method d) Rt=2.29min；MS m/z:366(M+H )+.BTK enzyme IC50=B
Example #3. (S)-N- (3,4- Dimethoxyphenyl) -6- (1- (ethenesulfonyl) pyrrolidin-3-yl)-[1,2,4] Triazole [1,5-a] pyrazine -8- amine
Step A. (S)-tert-butyl 3- (8- ((3,4- Dimethoxyphenyl) amino)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) pyrrolidine -1- formic acid esters and (R)-tert-butyl 3- (8- ((3,4- Dimethoxyphenyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters
To interpolation tert-butyl in the 10%Pd/C (0.50g, 0.40mmol) of the drying in 250mL stainless steel pressure bottle 3- (8- ((3,4- Dimethoxyphenyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) -2,5- dihydro -1H- pyrroles - 1- formic acid esters (1.00g, 2.28mmol, using B 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine [Noah's ark drugmaker], Using C with tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -2,5- dihydro -1H- pyrroles - 1- formic acid esters [Kang Beibo Ces Co., Ltd]), MeOH (100mL) and AcOH (4mL) preparation.H in 50psi2Under, at room temperature, Stir this mixture.After 3 days, this mixture is passed through nylon membrane overanxious and concentrate under reduced pressure.By the 0- in DCM 100%DCM/MeOH/NH4OH(950:45:5) silica gel chromatography of eluting carries out purification to this roughage.Merge and comprise product Fraction, and concentrate under reduced pressure, and be dried under vacuum to provide the racemic mixture of product at about 70 DEG C (0.72g).This compound is separated to provide (S)-tert-butyl 3- (8- ((3,4- by chiral preparative-SFC (table 2, method 2) Dimethoxyphenyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters (0.26g, 26%) and (R)-tert-butyl 3- (8- ((3,4- Dimethoxyphenyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine - 1- formic acid esters (0.32g, 32%) [spatial chemistry is any distribution].LC/MS (table 1, method e) Rt=1.45min.；MS m/ z:441(M+H)+.
Step B. (S)-N- (3,4- Dimethoxyphenyl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -8- amine
To (S)-tert-butyl 3- (8- ((3,4- Dimethoxyphenyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- Base) solution in MeOH (2.0mL) for the pyrrolidine -1- formic acid esters (0.25g, 0.568mmol, spatial chemistry is any distribution) Middle interpolation HCl (4M in Isosorbide-5-Nitrae-dioxane, 2.0mL, 8.00mmol).This reactant mixture is stirred at room temperature about 4h, so Concentrate under reduced pressure afterwards.This residue is dissolved in DCM/MeOH/NH4In OH, and it is concentrated on silica gel (1g), by being used in 100%DCM/MeOH/NH is maintained for a long time in DCM4OH(90:9:1) 0-100%DCM/MeOH/NH4OH(90:9:1) The silica gel of eluting carries out purification.Merge the fraction comprising product, concentrate, and be dried under vacuum to be given in ash at about 70 DEG C (S)-N- (3,4- Dimethoxyphenyl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- of white solid Amine (0.15g, 78%)：LC/MS (table 1, method e) Rt=1.45min.；MS m/z:341(M+H)+.
Step C. (S)-N- (3,4- Dimethoxyphenyl) -6- (1- (ethenesulfonyl) pyrrolidin-3-yl)-[1,2,4] Triazole [1,5-a] pyrazine -8- amine
At about 0 DEG C, to (S)-N- (3,4- Dimethoxyphenyl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5- A] pyrazine -8- amine (0.073g, 0.21mmol) and DIEA (0.093mL, 0.54mmol) add in the solution in DMA (1.5mL) Plus ethenesulfonyl chloride (0.025mL, 0.22mmol).After about 20min, this reactant mixture is lentamente stirred and is added to frozen water In (about 10mL).After this ice melts completely, be collected by vacuum filtration the solid obtaining and be dried under vacuum at 55 DEG C with Provide impure product.This solid is ground with MeOH (1mL).It is collected by vacuum filtration the solid obtaining simultaneously with other MeOH (1mL) is washed and is dried in a vacuum at 55 DEG C to be provided the solid with little purity change by LCMS.Should Filtrate and solid reconsolidate, and concentrate under reduced pressure and are carried out by the silica gel chromatography of the 0-5%MeOH eluting in DCM Purification.The fraction comprising product is concentrated under reduced pressure and is dried in a vacuum to provide white solid at about 55 DEG C (S)-N- (3,4- Dimethoxyphenyl) -6- (1- (ethenesulfonyl) pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -8- amine (0.024g, 26%)：LC/MS (table 1, method e) Rt=2.00min.；MS m/z:431(M+H)+.BTK enzyme IC50= A.
Example #4：1- (R) -3- [8- (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base amino)-[1,2, 4] triazole [1,5-a] pyridine -6- base]-pyrrolidin-1-yl }-propenone
Step A：N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1, 4] piperazine -2- amine
Add the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine (21.5g, 64.7mmol, example #1, step A), 6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (9.91g, 71.2mmol prepare #1), (9,9- dimethyl -9H- Ton -4,5- diyl) double (diphenylphosphine) (6.74g, 11.65mmol), diacetoxy palladium (1.308g, 5.83mmol) and Before cesium carbonate (63.3g, 194mmol), flask is filled with Isosorbide-5-Nitrae-dioxane (129mL) and with nitrogen degasification 10min.This is anti- Answer mixture nitrogen degasification about 10min, and be then heated to about 120 DEG C and last about 1h.This reaction is cooled to ambient temperature And lentamente add 400mL water and be stirred vigorously.The precipitation obtaining is filtered and is dried overnight to provide N- in vacuum drying oven (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- amine (23.8g, 102%, 85% purity)：LC/MS (table 1, method l) Rt=1.79min.；MSm/z:292,294(M+H)+.
Step B：Tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2, 4] triazole [1,5-a] pyridine -6- base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters
The 2L 3- neck flask of drying is filled with N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- two Hydrogen -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (23g, 79mmol), tert-butyl 3- (4,4,5,5- tetramethyl -1,3- dioxy Penta ring -2- base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (40.0g, 134mmol, Kang Beibo Ces Co., Ltd), Isosorbide-5-Nitrae-dioxane (330mL) with solution (40.3g, 190mmol) in water (66.0mL) for the potassium phosphate.This reaction is carried out bubbling 25min with argon, Subsequently add Xphos ring palladium G1 (2.92g, 3.96mmol).This reactant mixture is carried out bubbling about 30min, Ran Houjia with argon Heat lasts about 80min to about 60 DEG C.This reaction is cooled to ambient temperature and is slowly added about 400mL water to reactant mixture In.The precipitation that obtain is collected by filtration and is dried in vacuum drying oven.Filter cake is absorbed in DCM (1L) and uses saline (350mL) wash, through anhydrous MgSO4It is dried, filter, and concentrate under reduced pressure.Then with about 200mL diethyl ether, this solid is entered Row grinds.Be collected by filtration the precipitation obtaining and in vacuum drying oven be dried with provide tert-butyl 3- (8- ((6,7- dihydro- 4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) -2,5- dihydro -1H- Pyrroles's -1- formic acid esters (31.3g, 93%)：LC/MS (table 1, method l) Rt=2.10min.；MS m/z:424(M+H)+.
Step C：(R)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino) - [1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine -1- formic acid esters and (S)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrrole Azoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine -1- formic acid esters
By EtOH (0.50mL) be added to tert-butyl 3- in 4mL pressure bottle (8- ((6,7- dihydro -4H- pyrazoles [5, 1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) -2,5- dihydro -1H- pyrroles's -1- formic acid In ester (5.24mg, 0.012mmol) and 20%wt. hydroxide palladium carbon (1.06mg, 7.55 μm of ol).At about 50 DEG C, this is mixed Compound stir about 2h under 60psi hydrogen.By kieselguhrPad filters out this catalyst and is subtracting remaining solvent Pressure concentrates.Carried by purification being carried out to this crude product mixture with the silica gel chromatography of 10%-60%EtOAc/DCM eluting For tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5- A] pyridine -6- base) pyrrolidine -1- formic acid esters (14.5g, 47%).Then pass through chiral preparative HPLC (table 2, method 9) to this Racemic mixture carry out purification with provide (R)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine - 2- yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine -1- formic acid esters (3.79g, 12%, OR=+) and (S)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) pyrrolidine -1- formic acid esters (4.67,15%, OR=-)：LC/MS (table 1, method l) Rt=2.03min.； MS m/z:426(M+H)+.
Step D：(R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2, 4] triazole [1,5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone
Flask is filled with (R)-tert-butyl 3- together with hydrogen chloride (4N in Isosorbide-5-Nitrae-dioxane, 21mL, 87mmol) (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Pyrrolidine -1- formic acid esters (3.7g, 8.70mmol) and Isosorbide-5-Nitrae-dioxane (43mL).This reaction is heated to about 35 DEG C last about 90min.This solvent is concentrated under reduced pressure.Remaining residue is absorbed in DCM (43mL) and is cooled to about -40 DEG C, connect Interpolation N- ethyl-N-iospropyl propyl- 2- amine (7.59mL, 43.5mmol) and acryloyl chloride (0.918mL, 11.30mmol).Will This reaction stir about 10min at about -40 DEG C.This solvent is concentrated under reduced pressure.By the silicon with 0-8%MeOH/DCM eluting Glue chromatography carries out purification to this thick residue.Then by using 10:1 volume ratio from MeCN this compound is recrystallized with Offer (R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone (2.4g, 72.7%OR=+)：LC/MS (table 1, method l) Rt= 1.41min.；MS m/z:380(M+H)+.BTK enzyme IC50=A
Example #5. (R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1, 2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone
Step A.N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1, 4] piperazine -2- amine
By the bromo- 6- of 8- chloro- [1,2,4] triazole [1, the 5-a] pyridine in Isosorbide-5-Nitrae-dioxane (5mL) (0.500g, 2.151mmol, example #1, step A), 6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.329g, 2.366mmol, prepare #1), Xantphos (0.261g, 0.452mmol), Pd (OAc)2(0.048g, 0.215mmol) and Cs2CO3(1.752g, 5.38mmol) carries out bubbling with nitrogen.Then, at about 120 DEG C, this solution is heated about in microwave 1.5h.This reactant mixture is cooled to room temperature, segmentation between DCM (3x20mL) and water (20mL).Merge these organic layers, Concentrate, purification is carried out by the silica gel of the 20%-60%EtOAc eluting in heptane and provides N- (chloro- [1,2,4] three of 6- Azoles [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.348g, 55.7%):LC/ MS (table 1, method l) Rt=1.82min.；MS m/z:291(M+H)+.
Step B. tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2, 4] triazole [1,5-a] pyridine -6- base) -5,6- dihydropyridine -1 (2H)-formic acid esters
Add N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrrole in 10mL microwave tube Azoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.576g, 1.981mmol), tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxies Heterocycle pentaborane -2- base) -5,6- dihydropyridine -1 (2H)-formic acid esters (0.858g, 2.77mmol, Ali chemical company), THF (3mL), MeOH (0.600mL) and 2M aqueouss sodium carbonate liquor (2.97mL, 5.94mmol).This mixture is roused with nitrogen Bubble, then add 1,1 '-bis- (diphenylphosphino) ferrocene-dichloro palladium (II) chloride dichloromethane complex (0.162g, 0.198mmol).By the sealing of this bottle and carry out bubbling with nitrogen again.At about 130 DEG C, by this reactant mixture in microwave Heating about 1h.This reactant mixture is passed through kieselguhrFilter, washed with DCM and MeOH, concentrate under reduced pressure. Be given in light brown admittedly by the residue that this obtains is carried out with the silica gel chromatography of 0-10%DCM/MeOH eluting with purification Body tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) -5,6- dihydropyridine -1 (2H)-formic acid esters (0.704g, 65.0%):LC/MS (table 1, method l) Rt= 2.19min.；MS m/z:438(M+H)+.
Step C. (S)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino) - [1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- formic acid esters and (R)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- formic acid esters
At about 45 DEG C, in the H of about 50 bars2Under, by tert-butyl 3- (8- ((6,7- dihydros -4H- pyrazoles [5,1-c] [1, 4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) -5,6- dihydropyridine -1 (2H)-formic acid esters (0.704g, 1.609mmol) solution in THF (15mL), MeOH (15mL) and AcOH (10mL) passes through has Pearlman Catalyst Ka SekateH type pipe last about 16h.LC/MS shows and converts completely.Will be dense under reduced pressure for this solvent Contracting.Then this racemic mixture is carried out separating to provide (S)-tert-butyl by chiral preparative HPLC (table 2, method 7) 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) piperidines -1- formic acid esters (0.050g, 7.07%) and (R)-tert-butyl 3- (8- ((6,7- dihydros -4H- pyrazoles [5,1-c] [1, 4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- formic acid esters (0.053g, 7.49%) are [vertical Body chemistry is any distribution].LC/MS (table 1, method l) Rt=2.17min.；MS m/z:440(M+H)+.
Step D. (R)-N- (6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- Pyrazoles [5,1-c] [1,4] piperazine -2- amine
Flask is filled with MeOH (3.0mL) and is cooled to about 0 DEG C.Deca chloroacetic chloride (0.364mL, 5.12mmol).Will This mixture is stirred at room temperature about 2h.Then add the solution to (R)-tert-butyl 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- formic acid esters (0.050g, In 0.114mmol).This reactant mixture is stirred at room temperature overnight.This reactant mixture is concentrated to be given in light (R)-N- (6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyridine -8- the base) -6,7- dihydro -4H- pyrazoles of yellow solid [5,1-c] [1,4] piperazine -2- amine.LC/MS (table 1, method l) Rt=1.12min；MS m/z:340(M+H)+.This roughage is not Other purification need to be carried out and can be used for next step.
Step E. (R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2, 4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone
Flask is filled with (R)-N- (6- (piperidines -3- base)-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- two Hydrogen -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.039g, 0.115mmol) and the TEA in THF (1.1mL) (0.072mL, 0.517mmol).In ice bath, this reactant mixture is cooled to about 0 DEG C.Interpolation acryloyl chloride (0.01mL, 0.126mmol).By this mixture stir about 20min, then it is diluted with water (1.0mL).This reactant mixture is passed through system (table 1, method k) carries out purification to provide (R) -1- (3- (8- ((6, the 7- dihydro -4H- pyrroles in pale solid to standby type-HPLC Azoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene - 1- ketone (0.016g, 35%, OR=+):LC/MS (table 1, method h) Rt=1.58min；MS m/z:394(M+H)+.BTK enzyme IC50 =A.
Example #6. (S) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone
Step A.6- bromo- N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine
Add 1- methyl isophthalic acid H- pyrazoles -4- to NaH (0.864g, 60%, 36mmol) in the mixture in THF (50mL) Amine (2.097g, 21.59mmol).By this mixture at about 0 DEG C stir about 0.5h.It is slowly added 6,8- bis- bromo- [1,2,4] three This reactant mixture is simultaneously existed by solution in THF (30mL) for azoles [1, the 5-a] pyrazine (5g, 17.99mmol, Noah's ark drugmaker) 1h is stirred at 0 DEG C.Add water (5mL).This mixture is concentrated to dryness.Following said method, to set up other two reaction mixed Compound.Merge all of three batches, add water (100mL).Extract this mixture with EtOAc (3 × 500mL).This is organic Through Na2SO4Be dried, concentrate under reduced pressure, by carried out with the silica gel chromatography of 25%-50%EtOAc/PE eluting purification with Be given white solid the bromo- N- of 6- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (12g, 76%):1H NMR (400MHz, DMSO-D6) δ ppm δ 10.71 (s, 1H), 8.59-8.56 (d, J=12,2H), 8.07 (s, 1H),7.76(s,1H),3.86(s,3H).
Step B. tert-butyl 3- (8- (1- methyl isophthalic acid H- pyrazoles -4- base amino)-[1,2,4] triazole [1,5-a] pyrazine -6- Base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters
To the bromo- N- of 6- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (5g, 17mmol) Add tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxy in the solution in 1.4- dioxane (90mL) and water (30mL) Heterocycle pentaborane -2- base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (10.04g, 34mmol, Kang Beibo Ces Co., Ltd), Cs2CO3(16.62g, 51mmol) and Pd (PPh3)2Cl2(0.747g, 1.7mmol).At about 120 DEG C, in N2Under protection, should Mixture stir about 12h.This reactant mixture is concentrated under reduced pressure.By the 25%-50%EtOAc eluting in PE Silica gel chromatography carries out purification to provide tert-butyl 3- (8- (the 1- methyl isophthalic acid H- pyrazoles -4- of white solid to this residue Base amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (4.5g, 69%)：1H NMR (400MHz, DMSO-D6) δ ppm 10.31-10.30 (d, J=4,1H), 8.55 (s, 1H), 8.37-8.30 (d, J=28, 1H), 8.13-8.10 (d, J=12,1H), 7.79-7.75 (d, J=16,1H), 6.67-6.64 (d, J=12,1H), 4.46- 4.43 (d, J=12,2H), 4.25 (s, 2H), 3.30 (s, 3H), 1.46-1.44 (d, J=8,9H).
Step C tert-butyl 3- (8- (1- methyl isophthalic acid H- pyrazoles -4- base amino)-[1,2,4] triazole [1,5-a] pyrazine -6- Base) pyrrolidine -1- formic acid esters
Under the protection of argon, to tert-butyl 3- (8- (1- methyl isophthalic acid H- pyrazoles -4- base amino)-[1,2,4] triazole [1,5- A] pyrazine -6- base) -2,5- dihydro -1H- pyrroles's -1- formic acid esters (4.5g, 11.77mmol) is in the solution in THF (500mL) Add Pd/C (4.5g, 10%, 4.23mmol).At room temperature, in H2Under (about 14psi), by this reactant mixture stir about 12h.This reactant mixture is passed through kieselguhrPad is filtered, and this filtrate is concentrated under reduced pressure to be given Tert-butyl 3- (8- (1- methyl isophthalic acid H- pyrazoles -4- base amino)-[1,2,4] triazole [1,5-a] pyrazine -6- of white solid Base) pyrrolidine -1- formic acid esters (4.16g, 92%)：LC/MS (table 1, method d) Rt=2.94min；MS m/z:385(M+H)+.
Step D. (S)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] Pyrazine -6- base) pyrrolidine -1- formic acid esters and (R)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2, 4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters
By tert-butyl 3- (8- (1- methyl isophthalic acid H- pyrazoles -4- base amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Pyrrolidine -1- formic acid esters carry out separating to provide white solid simultaneously by chiral preparative HPLC (table 2, method 6) (S)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrroles Alkane -1- formic acid esters (0.435g, 40.2%, OR=+) and (R)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) ammonia Base)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- formic acid esters (0.442g, 40.9%, OR=-).[three-dimensional Be any distribution].LC/MS (table 1, method l) Rt=1.96min.；MS m/z:385(M+H)+.
Step E. (S)-N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] Pyrazine -8- amine
Flask is filled with MeOH (30mL) and is cooled to about 0 DEG C.Deca chloroacetic chloride (3.60mL, 50.9mmol).Should Mixture is stirred at room temperature about 2h.Then add the solution to (S)-tert-butyl 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- Base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) in pyrrolidine -1- formic acid esters (0.435g, 1.132mmol).Should Reactant mixture is stirred at room temperature about 3h.Remove solvent be given (S)-N- in pale solid (1- methyl isophthalic acid H- pyrazoles- 4- yl) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- amine.LC/MS (table 1, method l) Rt= 0.99min；MS m/z:285(M+H)+.This roughage is not required to carry out other purification can be used for next step.
Step F. (S) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine - 6- yl) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone
To (S)-N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- (pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine - 8- amine (0.200g, 0.703mmol), TEA (0.49mL, 3.52mmol) add acryloyl chloride in the solution in DMF (3.5mL) (0.057mL, 0.703mmol).This reactant mixture is stirred at room temperature about 30min.Add water (1.5mL) anti-so that this is quenched Should.This mixture is passed through preparative-HPLC, and (table 1, method k) carries out purification to provide (S) -1- (3- (8- of white solid ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene - 1- ketone (0.075g, 31%, OR=+):LC/MS (table 1, method h) Rt=1.42min；MS m/z:339(M+H)+.BTK enzyme IC50 =A.
Example #7：N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] Pyridine -6- base) cyclopenta) acrylamide
Step A：The chloro- N- of 6- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine
Cesium carbonate (42.0g, 129mmol) is added in Isosorbide-5-Nitrae-dioxane (238mL) to provide white suspension.Should Mixture carries out degasification with nitrogen, then in order rapidly respectively by chloro- for bromo- for 8- 6- [1,2,4] triazole [1,5-a] pyridine (10g, 43.0mmol) (example #1 step A), (9,9- dimethyl -9H- cluck ton -4,5- diyl) double (diphenylphosphine) (4.98g, 8.60mmol) it is added to this mixture with 1- methyl isophthalic acid H- pyrazoles -3- amine (3.66mL, 43.0mmol) (Kang Beibo Ces Co., Ltd) In.This mixture is carried out degasification with nitrogen, add diacetoxy palladium (0.966g, 4.30mmol).Will be further for this mixture Carry out degasification with nitrogen and heat about 1h at about 120 DEG C.This mixture is allowed to be cooled to room temperature and add EtOAc (250mL).Stir Mix this mixture and pass through kieselguhrFilter, washed with EtOAc (5x50mL), and concentrated to provide nigecose Slurry, this nigecose is starched segmentation between DCM (250mL) and water (100mL).Discharge this organic layer, extracted by DCM (100mL) This aqueous layer, the DCM layer that these are merged is dried over sodium sulfate, is filtered and is concentrated to provide nigecose to starch, this nigecose is starched It is deposited on silica gel (75g), carried by carrying out purification with the silica gel chromatography that gradient is 20%-55%EtOAc/ heptane eluting For the chloro- N- of 6- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine (6.9g, 64.5%):LC/MS (table 1, method a) Rt=1.81min；MS m/z 249(M+H)+.
Step B：(6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) (1- methyl isophthalic acid H- pyrazole-3-yl) carbamic acid The tert-butyl ester
By chloro- for 6- N- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine (5g, 20.11mmol) merge with mixture in DCM (101mL) for the di-tert-butyl dicarbonate (8.78g, 40.2mmol) To provide yellow solution.Add N, this reactant mixture is simultaneously existed by N- lutidines -4- amine (0.123g, 1.005mmol) Stir about 18h under room temperature.This mixture is concentrated to provide yellow solid, by this yellow solid and EtOAc (200mL) and 2-MeTHF (50mL) mixes, with citric acid (10% in water, 2x75mL), the aqueous sodium bicarbonate (4x60mL) of saturation and salt Water (60mL) is washed.Add DCM (100mL) in this organic layer, and this solution is dried through magnesium sulfate (13.7g), enter Row filters and concentrates to provide (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) (1- methyl isophthalic acid H- pyrazole-3-yl) amino T-butyl formate (7.11g, 100%):LC/MS (table 1, method a) Rt=1.94min；MS m/z 349(M+H)+.
Step C：(1- methyl isophthalic acid H- pyrazole-3-yl) (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base)-[1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate
By potassium acetate (5.99g, 61.1mmol) and (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) (1- methyl - 1H- pyrazole-3-yl) t-butyl carbamate (7.1g, 20.36mmol) is added in Isosorbide-5-Nitrae-dioxane (70.9mL) to provide orange Color suspension.Then will double (pinacol) two boron (12.92g, 50.9mmol) and XPhos with nitrogen degasification by this mixture (0.776g, 1.628mmol) is quickly added in this mixture in order.By the nitrogen degasification of this mixture, add Pd2 (dba)3(0.373g, 0.407mmol), then the nitrogen degasification of this mixture heats about 18h at about 110 DEG C.Allow this anti- Answer mixture to be cooled to room temperature and add DCM (30mL) and be stirred, this mixture is diluted with EtOAc (100mL), passes through KieselguhrFilter, and washed by EtOAc (5x30mL), and concentrated to provide red solid.Should Solid dissolving in DCM (120mL) and heptane (120mL), by this red solution concentrate under reduced pressure with remove most of DCM and Some heptane.The suspension obtaining is filtered, is washed with heptane (3x10mL), be dried to provide in vacuum drying oven (1- methyl isophthalic acid H- pyrazole-3-yl) (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base)-[1,2,4] three Azoles [1,5-a] pyridine -8- base) t-butyl carbamate (8.765g, 98%):LC/MS (table 1, method a) Rt=1.42min；MS m/z 441(M+H)+.
Step D：(1- methyl isophthalic acid H- pyrazole-3-yl) (6- (3- oxo ring amyl- 1- alkene -1- base)-[1,2,4] triazole [1,5- A] pyridine -8- base) t-butyl carbamate
By (1- methyl isophthalic acid H- pyrazole-3-yl) (6- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) - [1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate (3.8g, 8.63mmol) is added to Isosorbide-5-Nitrae-dioxane (28.8mL) to provide the yellow solution of muddiness in.Potassium phosphate (5.50g, 25.9mmol) in water (9.59mL) is added to In this solution.By the nitrogen degasification of this reactant mixture, add XPhos ring palladium (0.319g, 0.432mmol) and use nitrogen degasification；So Rapidly add the amyl- 2- ketenes of 3- bromine ring (2.62mL, 23.91mmol) (Shuande Xian Da company (SynTech)) afterwards in Isosorbide-5-Nitrae-two Solution in alkane (3x6mL).By the nitrogen degasification of this mixture, then at about 60 DEG C, heat about 18h.By this reactant mixture It is cooled to room temperature and be diluted, by kieselguhr with DCM (100mL)Filtered, entered with DCM (5x30mL) Row washing, concentrates to provide brown syrup, this brown syrup is deposited on silica gel (20g), by being 2% to 5% with gradient The silica gel chromatography of MeOH/DCM eluting carries out purification to provide (1- methyl isophthalic acid H- pyrazole-3-yl) (6- (amyl- 1- of 3- oxo ring Alkene -1- base)-[1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate (2.54g, 73%)：LC/MS (table 1, side Method a) Rt=1.63min；MS m/z 395(M+H)+.
Step E：(S)-(1- methyl isophthalic acid H- pyrazole-3-yl) (6- (3- oxocyclopentyl)-[1,2,4] triazole [1,5-a] pyrrole Pyridine -8- base) t-butyl carbamate
By (2R, 5R) -5- benzyl -3- methyl -2- (5- methylfuran -2- base) imidazoline -4- ketone (0.014g, 0.051mmol) with (1- methyl isophthalic acid H- pyrazole-3-yl) (6- (3- oxo ring amyl- 1- alkene -1- base)-[1,2,4] triazole [1,5-a] Pyridine -8- base) t-butyl carbamate (0.1g, 0.254mmol) is added in THF (0.507mL) to provide yellow suspension. This mixture is cooled to about 0 DEG C in ice bath.Add diethyl 2,6- dimethyl -1,4- dihydropyridine -3,5- dicarboxylic acid esters (0.077g, 0.304mmol) and trichloroacetic acid (5.11 μ L, 0.051mmol).By this mixture stir about 44h, by environment sky Gas heats cooling bath.Then slightly carry out purification by the silica gel chromatography that is 0 to 5%MeOH/DCM eluting with gradient to this to carry For (S)-(1- methyl isophthalic acid H- pyrazole-3-yl) (6- (3- oxocyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) amino T-butyl formate (0.088g, 88%, OR=bears) [spatial chemistry is any distribution]：LC/MS (table 1, method a) Rt= 1.65min；MS m/z 397(M+H)+.
Step F：(6- ((1S, 3R) -3- ((R) -1,1- dimethyl ethyl sulfonamido) cyclopenta)-[1,2,4] triazole [1,5-a] pyridine -8- base) (1- methyl isophthalic acid H- pyrazole-3-yl) t-butyl carbamate
By (S)-(1- methyl isophthalic acid H- pyrazole-3-yl) (6- (3- oxocyclopentyl)-[1,2,4] triazole [1,5-a] pyridine- 8- yl) t-butyl carbamate (14g, 35.3mmol) and (R) -2- methyl propyl- 2- sulfanilamide (6.42g, 53.0mmol) be added to To provide orange solution in THF (72.7mL).By the nitrogen degasification of this mixture, then add purity titanium tetraethoxide (24.17g, 106mmol), this solution is heated about 18h at about 50 DEG C.This reactant mixture is cooled to room temperature, then be dried ice/ In MeCN bath, this solution is cooled to about -50 DEG C, disposably adds sodium borohydride (1.924g, 50.9mmol)；Stir this reaction Mixture is simultaneously gradually heated up cooling bath through the 4h time period.The red solution obtaining is added drop-wise to the watersoluble chlorinated sodium stirring In solution (24%, 400mL).Add THF (100mL) and 2-MeTHF (200mL) and by this solution stirring about 1h.By this upper strata Organic layer is decanted by suction, adds 2-MeTHF (200mL) stir about 30min in this waterborne suspension, then passes through silicon Diatomaceous earthFilter, washed with 2-MeTHF (4x50mL), this filtrate segmentation merges this organic layer, with the water of saturation Property sodium bicarbonate (2x100mL) and saline (100mL) washing, dried over magnesium sulfate, filter and concentrate to provide 20g yellow solid Body, this yellow solid is passed through to be carried out purification and provide for the silica gel chromatography of 0 to 6.5%MeOH/DCM eluting with gradient 14.6g yellow solid.This mixture is passed through chiral preparative (table 2, method 8) separate to provide (6- ((1S, 3R) -3- ((R) -1,1- dimethyl ethyl sulfonamido) cyclopenta)-[1,2,4] triazole [1,5-a] pyridine -8- base) (1- methyl isophthalic acid H- Pyrazole-3-yl) t-butyl carbamate (7.0g, 39.5%, OR=bears) [spatial chemistry is any distribution]：LC/MS (table 1, Method a) Rt=1.90min；MS m/z 502(M+H)+.
Step G：6- ((1S, 3R) -3- amino cyclopentyl)-N- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1, 5-a] pyridine -8- amine hydrochlorate
Will (6- ((1S, 3R) -3- ((R) -1,1- dimethyl ethyl sulfonamido) cyclopenta)-[1,2,4] triazole [1, 5-a] pyridine -8- base) (1- methyl isophthalic acid H- pyrazole-3-yl) t-butyl carbamate (5.5g, 10.96mmol) is added to MeOH (22.02mL) to provide yellow solution in.In ice bath, this solution is cooled to about 0 DEG C.Via charging hopper Deca hydrochloric acid (3.0M is in cyclopentyl-methyl ether) (43.9mL, 132mmol).Remove this ice bath after stir about 1h, then this mixture exists Stir about 18h under room temperature.Add ether (100mL) and by this solution stirring 1h.Add ether (50mL) should in this suspension Mixture is filtered.The solid collected is rinsed with ether (5x20mL), 1h is dried to provide 6- ((1S, 3R) -3- amino ring Amyl group)-N- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- amine hydrochlorate:LC/MS (table 1, side Method a) Rt=1.04min；MS m/z 298(M+H)+.It is used in next step as former state.
Step H：N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] Pyridine -6- base) cyclopenta) acrylamide
By 6- ((1S, 3R) -3- amino cyclopentyl)-N- (1- methyl isophthalic acid H- pyrazole-3-yl)-[1,2,4] triazole [1,5-a] Pyridine -8- amine hydrochlorate (3.66g, 10.96mmol) is added in 2-MeTHF (60mL) to provide white suspension.This is mixed Compound is cooled to about 0 DEG C in ice bath.By Dropping funnel Deca potassium dihydrogen phosphate (22.91g, 132mmol) at water (70mL) In solution and by this mixture stir about 10min.By syringe through about 15min Deca acryloyl chloride (0.890mL, 10.96mmol) the solution in 2-MeTHF (10mL), by this reactant mixture at about 0 DEG C stir about 30min.This is mixed Thing segmentation, discharges this aqueous layer, and this organic layer is washed with the aqueous sodium bicarbonate (2x50mL) of saturation, saline (50mL) Wash, dried over sodium sulfate, filter and concentrate to provide 3.63g faint yellow solid.Add MeCN (40mL) and this suspension is stirred Mix about 1h, then filtered, by the solid collected with ice-cold MeCN (4x10mL), pentane (7x20mL) be rinsed with N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) is provided Cyclopenta) acrylamide (2.5g, 64.9%OR=are just) [spatial chemistry is any distribution]：LC/MS (table 1, method a) Rt= 1.48min；MS m/z 352(M+H)+.BTK enzyme IC50=A
Example #8：N- ((1R, 3S) -3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino) - [1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide and N- ((1S, 3R) -3- (8- ((6,7- dihydro -4H- pyrrole Azoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide
Step A：N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1, 4] piperazine -2- amine
To in microwave reaction bottle add the bromo- 6- of tert-butyl 8- chloro- [1,2,4] triazole [1,5-a] pyridine (1.0g, 4.3mmol, example #1, step A), 6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.658g, 4.73mmol, Preparation #1), 1,4- dioxane (10mL), Cs2CO3(2.80g, 8.60mmol), Xantphos (0.124g, 0.215mmol) and Pd2(dba)3(0.197g, 0.215mmol).This reaction bottle is rinsed with nitrogen, adds a cover, stir and in Biotage microwave reaction It is heated to about 120 DEG C in device and last about 3h.This reactant mixture is diluted with DCM (80mL) and water (50mL).Separating should Organic layer, is washed with water (50mL), saline (50mL), and through Na2SO4It is dried.This organic layer is filtered, dense under reduced pressure Contract and carry out purification to provide the N- (6- in yellow solid by using the silica gel chromatography of the 5%MeOH eluting in DCM Chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.85g, 61.2%)：LC/MS (table 1, method m) Rt=1.56min；MS m/z 291(M+H)+.
Step B：(6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- base) t-butyl carbamate
By N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine (2.0g, 6.9mmol), BoC2O (4.79mL, 20.6mmol), TEA (2.88mL, 20.6mmol) and DMAP (0.840g, 6.88mmol) mixture in DCM (100mL) is stirred at room temperature overnight.By this organic layer saturation NH4Cl (3x50mL) is washed.By organic layer Na2SO is dried, filters and concentrated under reduced pressure.By this crude product From petroleum ether (60 DEG C to 90 DEG C) recrystallization to provide (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- in yellow solid Base) (6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (2.5g, 86%):LC/MS (table 1, method n) Rt=1.72min；MS m/z 391(M+H)+.
Step C：(6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) (6- (3- oxo ring amyl- 1- alkene -1- Base)-[1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate
Round-bottomed flask is filled with (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (0.05g, 0.13mmol), dicyclohexyl (2', 6'- dimethoxy - [1,1'- diphenyl] -2- base) phosphine (0.016g, 0.038mmol), potassium phosphate (0.081g, 0.38mmol), water (0.4mL) and first Benzene (4mL).By the nitrogen degasification of this reactant mixture, subsequently add 3- (4,4,5,5- tetramethyl -1,3,2- dioxane penta boron Alkane -2- base) ring amyl- 2- ketenes (0.035g, 0.17mmol, US 20120077814) and Pd2(dba)3(0.012g, 0.013mmol).In Biotage microwave, at about 100 DEG C, this suspension is heated about 2h.This mixture is passed through post color Spectrometry (DCM:MeOH=40:1) carry out purification to provide (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) (6- (3- oxo ring amyl- 1- alkene -1- base)-[1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate (0.03g, 53.7%):LC/MS (table 1, method r) Rt=1.57min；MS m/z 437(M+H)+.
Step D：(6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) (6- (3- oxocyclopentyl)-[1,2, 4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate
Round-bottomed flask is filled with (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- in MeOH (15mL) Base) (6- (3- oxo ring amyl- 1- alkene -1- base)-[1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate (0.04g, 0.09mmol), subsequently adds 10%Pd/C (0.010g, 0.092mmol).At room temperature by this suspension in hydrogen Stir 1 day under atmosphere.This suspension is filtered, and filtrate is concentrated under reduced pressure to provide (6,7- dihydro -4H- pyrazoles [5,1- C] [1,4] piperazine -2- base) (6- (3- oxocyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) t-butyl carbamate (0.03g, 75%):LC/MS (table 1, method r) Rt=1.57min；MS m/z 439(M+H)+.
Step E：(6- (3- (benzylamino) cyclopenta)-[1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro - 4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) t-butyl carbamate
By (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) (6- (3- oxocyclopentyl)-[1,2,4] three Azoles [1,5-a] pyridine -8- base) solution AcOH in DCM (10mL) for the t-butyl carbamate (0.080g, 0.18mmol) (0.01mL, 0.182mmol) is processed, and subsequently uses phenylmethanamine (0.098g, 0.91mmol) to process.Under nitrogen at room temperature After stir about 20min, add sodium triacetoxy borohydride (0.193g, 0.912mmol) and continue to be stirred overnight.Add MeOH (2mL), the NaCl (10mL) of DCM (10mL) and saturation these layers of separation.This aqueous layer is extracted with DCM (10mL).Should Product preparative-TLC purification is to provide (6- (3- (benzylamino) cyclopenta)-[1,2,4] triazole [1,5-a] pyridine -8- Base) (6,7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (0.03g, 27.9%):LC/MS (table 1, method m) Rt=1.81,1.83min；MS m/z 530(M+H)+.
Step F：(6- (3- amino cyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) t-butyl carbamate
By (6- (3- (benzylamino) cyclopenta)-[1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- dihydro -4H- pyrrole Azoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (0.040g, 0.076mmol), 10%Pd/C (0.10g, 0.944mmol) flow back under nitrogen about 2h with mixture in MeOH (20mL) for the ammonium formate (0.30g, 4.8mmol).This is anti- Mixture is answered to cool down, by kieselguhrFilter, and concentrate.NaCl (30mL) dilution by this residue saturation And extracted with DCM (3x30mL).The organic layer merging is washed with water (50mL) and saline (50mL), then through anhydrous sodium sulfate It is dried, filtered and concentrated to provide thick (6- (3- amino cyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- bis- Hydrogen -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (0.025g, 52.7%):LC/MS (table 1, method m)Rt=1.39min；MS m/z 440(M+H)+.
Step G：N- (6- (3- amino cyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrrole Azoles [5,1-c] [1,4] piperazine -2- amine
Round-bottomed flask is filled with (6- (3- amino cyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) (6,7- bis- Hydrogen -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- base) t-butyl carbamate (0.120g, 0.273mmol) and MeOH (6mL). Add solution in dioxane (0.010mL, 0.28mmol) for the 4M Hcl and this reaction is stirred at room temperature about 4h.This is molten Liquid be concentrated to dryness be given N- (6- (3- amino cyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro - 4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.085g, 60%):LC/MS (table 1, method m) Rt=1.24min；MS m/z 340(M+H)+.
Step H：N- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] three Azoles [1,5-a] pyridine -6- base) cyclopenta) acrylamide
Round-bottomed flask is filled with N- (6- (3- amino cyclopentyl)-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- Dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine hydrochlorate (0.102g, 0.271mmol) and DCM (6mL) by this solution It is cooled to about 0 DEG C.Add TEA (0.378mL, 2.71mmol) and by this solution stirring about 10min, subsequent Deca in this flask Solution in DCM (0.1mL) for the acryloyl chloride (0.032g, 0.353mmol).By this mixture stir about 20min.Then should Reaction solution concentrates under reduced pressure to provide N- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) ammonia Base)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide (0.05g, 46.8%):LC/MS (table 1, method m)Rt=1.42min；MS m/z 394(M+H)+.
Step I：N- ((1R, 3S) -3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino) - [1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide and N- ((1S, 3R) -3- (8- ((6,7- dihydro -4H- pyrrole Azoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide
By N- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide (0.53g, 1.4mmol) pass through chiral preparative HPLC (table 2, method 13) Separate be given N- ((1S, 3R) -3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2, 4] triazole [1,5-a] pyridine -6- base) cyclopenta) acrylamide (0.036g, 7%, OR=bears).BTK enzyme IC50=A
By remaining mixture pass through chiral preparative HPLC (table 2, method 14) again purification be given N- ((1R, 3S)- 3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- Base) cyclopenta) acrylamide (0.033g, 17%, OR=just):LC/MS (table 1, method m) Rt=1.42min；MS m/z 394 (M+H)+.BTK enzyme IC50=A
Example #9：N- ((1S, 3R) -3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Pyridine -6- base) cyclopenta) acrylamide and N- ((1R, 3S) -3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] three Azoles [1,5-a] pyridine -6- base) cyclopenta) acrylamide
Step A：The chloro- N- of 6- (5- morpholino pyridine -2- base)-[1,2,4] triazole [1,5-a] pyridine -8- amine
Reaction bottle is filled with the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine (0.500g, 2.15mmol, reality Example #1, step A), 5- morpholino pyridine -2- amine (0.385g, 2.15mmol, Noah's ark drugmaker), Isosorbide-5-Nitrae-dioxane (10mL), Cs2CO3(1.40g, 4.30mmol), Xantphos (0.0622g, 0.108mmol) and Pd2(dba)3(0.098g, 0.11mmol).This reaction bottle is rinsed with nitrogen, adds a cover, be stirred and heated to about 120 DEG C overnight.This reaction is cooled to room Temperature and and then use DCM (100mL) and water (80mL) to dilute.Separate this organic layer, washed with water (80mL), saline (100mL), And through Na2SO4It is dried.After extract is concentrated to dryness, it is 20%-50%EtOAc eluting by the gradient in petroleum ether Silica gel chromatography this product is carried out with purification to provide the chloro- N- of 6- (5- morpholino pyridine -2- base)-[1,2,4] triazole [1,5- A] pyridine -8- amine (0.50g, 70.3%):LC/MS (table 1, method r) Rt=1.75min；MS m/z 331(M+H)+.
Step B：4- ((t-butoxy carbonyl) amino) ring amyl- 1- alkene -1- base trifluoro-methanyl sulfonate
At about -78 DEG C, LDA (37.6mL, 75mmol, 2M) is added to (3- oxocyclopentyl) t-butyl carbamate (6g, 30.1mmol, Noah's ark drugmaker) is in the solution in THF (2mL).After about 20min, it is added in THF (50mL) 1,1,1- tri- fluoro- N- phenyl-N- ((trifluoromethyl) sulfonyl) Methanesulfomide (11.83g, 33.1mmol) is simultaneously removing cooling bath Continue the other 10min of stir about before and allow this mixture to reach room temperature.After about 2.5h, by this mixture Et2O dilutes And washed with 1N aqueous sodium hydroxide and 1N aqueouss hydrochloric acid in order.By this solution through MgSO4It is dried, concentrate under reduced pressure And intermediate 4- ((t-butoxy carbonyl) amino) ring amyl- 1- alkene -1- base fluoroform is provided by purified by flash chromatography Sulfonate (1.4g, 14%) simultaneously proceeds immediately.Round-bottomed flask is filled with 4- ((t-butoxy carbonyl) amino) ring amyl- 1- alkene -1- base trifluoro-methanyl sulfonate (0.6g, 1.811mmol), DPPF (0.050g, 0.091mmol) and in Isosorbide-5-Nitrae-dioxane (10mL) PdCl in2(dppf)-CH2Cl2Adduct (0.074g, 0.091mmol) is to provide brown suspension.Add acetic acid Potassium (0.53g, 5.4mmol) and double (pinacol) two boron (0.460g, 1.81mmol).By the mixture obtaining at about 100 DEG C It is heated overnight.(3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- is provided by the product that post separation is wanted Base) ring amyl- 3- alkene -1- base) t-butyl carbamate (0.36g, 64%):LC/MS (table 1, method s) Rt=1.85min；MS m/z 310(M+H)+.
Step C：(3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) ring Amyl- 3- alkene -1- base) t-butyl carbamate
In 10mL microwave reaction bottle, by chloro- for 6- N- (5- morpholino pyridine -2- base)-[1,2,4] triazole [1,5-a] Pyridine -8- amine (0.30g, 0.91mmol), (3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) ring is amyl- 3- alkene -1- base) t-butyl carbamate (0.393g, 1.27mmol), PdCl2(dppf) (0.066g, 0.091mmol) and K2CO3 (0.91mL, 2.72mmol) mixture in Isosorbide-5-Nitrae-dioxane (4mL) is heated to about 130 DEG C and lasts about 3h.By this mixture It is cooled to room temperature and DCM (150mL) is added in this solution.This organic layer is washed with the NaCl (3x50mL) of saturation.Will This organic layer is through Na2SO4It is dried, filter and concentrate.This crude product is given in Light brown solid by preparative-TLC purification (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) ring amyl- 3- alkene -1- base) T-butyl carbamate (0.35g, 66.3%):LC/MS (table 1, method m) Rt=1.77min；MS m/z 478(M+H)+.
Step D：(3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) ring Amyl group) t-butyl carbamate
Round-bottomed flask is filled with (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Pyridine -6- base) ring amyl- 3- alkene -1- base) solution in MeOH (100mL) for the t-butyl carbamate (0.350g, 0.733mmol), Subsequently add 10%Pd/C (0.050g, 0.47mmol).At room temperature, by this suspension stir about 1 day in a hydrogen atmosphere.Will This suspension filters, and this filtrate is concentrated under reduced pressure being given (3- (8- ((5- morpholino pyridine -2- base) amino)-[1, 2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) t-butyl carbamate (0.310g, 88%):LC/MS (table 1, method m) Rt=1.76min；MS m/z 480(M+H)+.
Step E：6- (3- amino cyclopentyl)-N- (5- morpholino pyridine -2- base)-[1,2,4] triazole [1,5-a] pyridine - 8- amine hydrochlorate
Solution in Isosorbide-5-Nitrae-dioxane for the 4M HCl (7mL, 28.0mmol) is added drop-wise to (3- (8- ((5- morpholino pyridine- 2- yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) t-butyl carbamate (0.310g, 0.646mmol) in the solution in THF (14mL).This mixture is stirred at room temperature about 3h.Under reduced pressure remove solvent with Provide 6- (3- amino cyclopentyl)-N- (5- morpholino pyridine -2- base)-[1,2,4] triazole [1,5-a] pyridine -8- amine hydrochlorate 0.22g, 81%):LC/MS (table 1, method n) Rt=1.38min；MS m/z 380(M+H)+.
Step F：N- (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-I] pyridine -6- base) Cyclopenta) acrylamide
At about 0 DEG C, TEA (0.073mL, 0.53mmol) is added drop-wise to 6- (3- amino cyclopentyl)-N- (5- morpholino pyrrole Pyridine -2- base)-[1,2,4] triazole [1,5-a] pyridine -8- amine hydrochlorate (0.219g, 0.527mmol) hanging in DCM (8mL) In supernatant liquid.By this solution stirring about 10min.Then Deca acryloyl chloride (0.062g, 0.68mmol) is molten in DCM (1mL) Liquid.Remove under reduced pressure by this mixture stir about 20min and by these solvents.This crude product is passed through preparative-HPLC pure Change to obtain N- (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) Acrylamide (0.17g, 74%):LC/MS (table 1, method n) Rt=1.56min；MS m/z 434(M+H)+.
Step G：N- ((1S, 3R) -3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Pyridine -6- base) cyclopenta) acrylamide and N- ((1R, 3S) -3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] three Azoles [1,5-a] pyridine -6- base) cyclopenta) acrylamide
By N- (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) ring penta Base) acrylamide (0.160g, 0.369mmol) pass through chiral preparative HPLC (table 2, method 15) purification be given N- ((1S, 3R) -3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) cyclopenta) acryloyl Amine (0.027g, 17%, OR=bears).BTK enzyme IC50=B
Remaining mixture (0.035g, 0.081mmol) is passed through chiral preparative HPLC (table 2, method 15) repurity To provide N- ((1R, 3S) -3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Cyclopenta) acrylamide (0.024g, 69%, OR=just):LC/MS (table 1, method m) Rt=1.49min；MS m/z 434(M+ H)+.BTK enzyme IC50=A
Example #10：(1R, 3R) -3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) Hexalin
Step A：The bromo- N- of 6- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine
Reaction bottle is filled with 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine (10.38g, 37.3mmol, Noah's ark Drugmaker), 1- methyl isophthalic acid H- pyrazoles -4- amine (3.989g, 41.1mmol, Ai Site company), DMF (100mL) and N- second Base-N- isopropyl propyl- 2- amine (12.92ml, 74.7mmol).This reaction bottle is rinsed with nitrogen, and is heated to about 100 DEG C of flushings About 90min.This reaction is cooled to room temperature and and then is dropped in the water (200mL) stirring by charging hopper.Will The suspension obtaining filters, and is washed with THF, then with 1:1EtOAc/ heptane wash is to provide the bromo- N- of 6- (1- methyl isophthalic acid H- pyrrole Azoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (9.8g, 87%):LC/MS (table 1, method b) Rt=1.66min； MS m/z 295(M+H)+.
Step B：3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) ring Hexyl -2- ketenes
By bromo- for 6- N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (1g, 3.40mmol), tert-butyl 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) cyclohexyl -2- ketenes (0.755g, 3.40mmol), PdCl2(dppf) (0.239g, 0.340mmol) and cesium carbonate (3.32g, 10.20mmol) is mixed Compound is dissolved in Isosorbide-5-Nitrae-dioxane (12mL) and water (4mL), and is heated to about 90 DEG C and lasts about 16h.This mixture is cooled down To room temperature and add water (5mL) to this solution.This suspension is filtered and uses water (10mL), heptane (9mL) and ether (6mL) Washing.There is provided in pale yellow colored solid by purification being carried out to remaining solid with the silica gel chromatography of 0-10%MeOH/DCM eluting 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) cyclohexyl -2- alkene of body Ketone (0.9g, 2.91mmol, 86% yield):LC/MS (table 1, method h) Rt=1.47min；MS m/z 310(M+H)+.
Step C：3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) ring Hexanone
Round-bottomed flask is filled with 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) solution in MeOH (2mL) for the cyclohexyl -2- ketenes (0.89g, 2.88mmol), subsequently adds 10%Pd/C (0.612g, 0.575mmol).At room temperature, by this suspension stir about 18h in a hydrogen atmosphere.This suspension is filtered, and This filtrate is provided 3- (8- ((1- methyl isophthalic acid H- pyrrole by carrying out purification with the silica gel chromatography of 0-8%MeOH/DCM eluting Azoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Ketohexamethylene (0.32g, 1.02mmol, 35% yield):LC/ MS (table 1, method h) Rt=1.54min；MS m/z 312(M+H)+.
Step D：3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) ring Hexanone
Round-bottomed flask is filled with 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) Ketohexamethylene (0.32g, 1.028mmol)) solution in THF (10.28mL) be cooled to about -78 DEG C.Deca L- Selctride (2.056ml, 2.056mmol) stir 1h in this reactant mixture and at about -78 DEG C then allow through 4h plus Heat is to room temperature.This reaction is quenched by adding the ammonium chloride (5mL) of aqueouss saturation, then uses DCM (3x5mL) to extract.To merge Organic layer concentrate under reduced pressure.By with the silica gel chromatography of 0-10%MeOH/DCM eluting, this roughage is carried out purification with Provide 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- in pale solid Base) Hexalin (0.27g, 84% yield):LC/MS (table 1, method h) Rt=1.45min；MS m/z 314(M+H)+.By 3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Hexalin (0.260g, 0.369mmol) by chiral preparative HPLC (table 2, method 16) carry out purification be given (1R, 3R) -3- (8- ((1- methyl - 1H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) Hexalin (0.08g, 24%, OR=bears).CSF- 1R enzyme IC50=A.
Example #11：(1R, 3R) -3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Piperazine -6- base) Hexalin
Step A：5- (hexamethylene -1- alkene -1- base) pyrazine -2- amine
Round-bottomed flask is filled with 5- bromo-pyrazine -2- amine (13.1g, 75mmol, Noah's ark drugmaker), 2- (hexamethylene -1- Alkene -1- base) -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes (15.7g, 75mmol, Kang Beibo Ces Co., Ltd) and Trivalent potassium phosphate (32g, 151mmol) in Isosorbide-5-Nitrae-dioxane (229mL) and water (22.86mL) mixture.This reaction is mixed Thing nitrogen degasification about 10min. is simultaneously heated to about 50 DEG C.Add Pd (PPh3)4(2.62g, 2.26mmol) this reaction is mixed Thing is heated to about 80 DEG C and lasts about 5h.By other Pd (PPh3)4(0.7mg) it is added in this reactant mixture and at about 80 DEG C Under be stirred overnight.This reactant is cooled to ambient temperature segmentation between EtOAc and saline (2x50mL).By having of merging Machine part is through anhydrous MgSO4It is dried, and filtered by silica gel plug.This solvent is concentrated in a vacuum.By this residue absorb to In EtOAc the and 50mL heptane of about 100mL.The solid collecting precipitation is to provide 5- (hexamethylene -1- alkene -1- base) pyrazine -2- amine (8.6g, 96% yield):LC/MS (table 1, method h) Rt=1.78min；MS m/z 176(M+H)+.
Step B：5- cyclohexyl pyrazine -2- amine
Round-bottomed flask is filled with 10%Pd/C carbon (3g, 39.9mmol) and wet EtOAc (5mL).By 5- (hexamethylene -1- alkene - 1- yl) solution in EtOH (256mL) and acetic acid (10.24mL) for the pyrazine -2- amine (7g, 39.9mmol) is added to and is fixed with hydrogen In the flask of balloon.By this reaction hydrogen purification and about 4h is stirred at room temperature.This reactant mixture is passed through kieselguhrPad filters and removes these solvents under reduced pressure.By the solid obtaining EtOAc and saturation aqueouss NaHCO3It Between segmentation.By the organic moiety merging through anhydrous MgSO4It is dried, filter, and be concentrated under vacuum.By with 0-80%EtOAc/ The silica gel chromatography of heptane eluting carries out purification to provide 5- cyclohexyl pyrazine -2- amine (1.4g, 19% yield) to this residue: LC/MS (table 1, method h) Rt=1.78min；MS m/z 178(M+H)+.
Step C：3- bromo- 5- cyclohexyl pyrazine -2- amine
In round-bottomed flask, N-bromo-succinimide (1.6g, 9.08mmol) is added batch-wise 5- cyclohexyl pyrazine -2- Amine (1.4g, 7.90mmol) is in the solution in DMF (15mL).This reaction is stirred at room temperature about 2h.Ice-cold by adding Water (30mL) this reaction is quenched.By this reaction EtOAc and saturation aqueouss NaHCO3Between segmentation, through anhydrous MgSO4Dry Dry, filtered by silicagel pad, and concentrate under reduced pressure to provide 3- bromo- 5- cyclohexyl pyrazine -2- amine (1.42g, 49% yield): LC/MS (table 1, method h) Rt=2.35min；MS m/z 256,258(M+H)+.
Step D：(E)-N'- (3- bromo- 5- cyclohexyl pyrazine -2- base)-N- carbonamidine hydroxysalt
In round-bottomed flask, bromo- for 3- 5- cyclohexyl pyrazine -2- amine (1.2g, 4.6mmol) is dissolved in N, N- dimethyl methyl In amide dimethylacetal (1.9mL, 13.82mmol).This mixture is heated to about 100 DEG C and lasts about 1h.This solvent is existed Concentrate to provide thick residue in vacuum.By this thick (E)-N'- (3- bromo- 5- cyclohexyl pyrazine -2- base)-N, N- dimethyl carbonamidine Salt (1.4g, 4.61mmol) is dissolved in MeOH (12mL) and is processed with oxammonium hydrochloride. (0.45g, 6.45mmol).This is reacted About 4h is stirred at room temperature.This solvent is concentrated under reduced pressure.100mL water is added in remaining residue, and by adding Plus 1M aqueouss NaOH adjust pH to 9.The solid of formation is filtered and collects to provide (E)-N'- (3- bromo- 5- cyclohexyl pyrrole Piperazine -2- base)-N- carbonamidine hydroxysalt (1.2g, 78% yield):LC/MS (table 1, method h) Rt=2.42min；MS m/z=299, 301(M+H)+.
Step E：8- bromo- 6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine
To (E)-N'- (3- bromo- 5- cyclohexyl pyrazine -2- base)-N- carbonamidine hydroxysalt (1.2g, 4.03mmol) in MeCN (20mL) add trifluoroacetic anhydride (0.85mL, 6.05mmol) in the solution in and this mixture is stirred at room temperature about 3h. By the segmentation between 1M NaOH and EtOAc of this reactant mixture.By the organic moiety merging through anhydrous Na2SO4It is dried, filter, And concentrate under reduced pressure.By with the silica gel chromatography of 0-100%EtOAc/ heptane eluting, this residual materials is carried out purification with 8- bromo- 6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine (0.75g, 61% yield) is provided:LC/MS (table 1, method h) Rt= 2.31min；MS m/z=281,283 (M+H)+.
Step F：1- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) -2- methyl propan-2-ol
Flask is filled with 8- bromo- 6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine (0.05g, 0.178mmol), 1- (4- amino -1H- pyrazol-1-yl) -2- methyl propan-2-ol (33.1mg, 0.213mmol prepare #3) and in DMF (2mL) N- ethyl-N-iospropyl propyl- 2- amine (0.046g, 0.356mmol).This reaction is stirred at 100 DEG C 12hr.By this reactant It is cooled to ambient temperature and (table 1, method u) purification is to provide 1- (4- ((the 6- hexamethylene of white solid by preparative-HPLC Base-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2- methyl propan-2-ol (0.03g, 48% product Rate):LC/MS (table 1, method v) Rt=3.12min；MS m/z=356 (M+H)+.CSF-1R enzyme IC50=A
Example #12：N- (6- cyclopenta-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5, 1-c] [1,4] piperazine -2- amine
Step A：1- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) -2- methyl propan-2-ol
To N- (6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine (0.07g, 0.241mmol, example 4, step A) is dripped by syringe in the solution in Isosorbide-5-Nitrae-dioxane (2.4mL) Plus the THF solution (2.9mL, 1.45mmol, AlfaAesar (Alfa Aesar)) of 0.5M cyclopenta zinc bromide.Adding Pd (dppf)Cl2Before (0.019g, 0.024mmol), by this reaction under nitrogen stir about 5min.This reaction is heated to 85 DEG C hold Continuous 4h.This reactant is cooled to ambient temperature aqueouss NaHCO in saturation3Segmentation and EtOAc (2x20mL) between.To close And organic moiety through anhydrous MgSO4It is dried, filter, and be concentrated under vacuum.By with 0-100%EtOAc/ heptane eluting Silica gel chromatography carries out purification to provide N- (6- cyclopenta-[1,2,4] triazole [1,5-a] pyridine -8- base) -6 to this roughage, 7- dihydro -4H- pyrazoles [5,1-c] [Isosorbide-5-Nitrae] piperazine -2- amine (0.036g, 41% yield).LC/MS (table 1, method h) Rt= 2.88min；MS m/z=325 (M+H)+.CSF-1R enzyme IC50=A
Example #13：1- (6- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) pyridin-3-yl) piperazine Pyridine -4- alcohol
Step A：1- (6- nitropyridine -3- base) piperidines -4- alcohol
By round-bottomed flask be filled with 5- bromo- 2- nitropyridine (4.0g, 19.7mmol), 4- hydroxy piperidine (2.4g, Potassium carbonate (5.5g, 39.4mmol) 23.6mmol) and in DMSO (5mL).This reaction is stirred at room temperature about 20h.Cross Filter the solid of formation and remaining filtrate is concentrated under reduced pressure.Remaining residue is ground with DCM to provide 1- (6- nitre Yl pyridines -3- base) piperidines -4- alcohol (1.89g, 43% yield).LC/MS (table 1, method h) Rt=1.24min；MS m/z=224 (M+H)+.
Step B：1- (6- aminopyridine -3- base) piperidines -4- alcohol
By rustless steel hydrogenation vessel be filled with 1- (6- nitropyridine -3- base) piperidines -4- alcohol (1.89g, 8.48mmol) and 10% palladium carbon (0.541g, 0.509mmol) in MeOH (200mL).At ambient temperature, by this mixture with hydrogen (about Shake in Parr hydrogenator 30psi) pressurizeing.After about 1h, this reactant mixture is passed through kieselguhrPad filters, Washed with excessive MeOH.By this solvent go in a vacuum divided by provide 1- (6- aminopyridine -3- base) piperidines -4- alcohol (1.55g, 95% yield).1H NMR (400MHz, DMSO-d6) δ 7.59 (dd, J=3.0,0.7Hz, 1H), 7.14 (dd, J=8.8, 3.0Hz, 1H), 6.37 (dd, J=8.9,0.7Hz, 1H), 5.33 (bs, 2H), 4.62 (d, J=3.9Hz, 1H), 3.54 (tq, J =8.3,3.9Hz, 1H), 3.24-3.13 (m, 2H), 2.62 (ddd, J=12.5,10.0,2.9Hz, 2H), 1.85-1.74 (m, 2H),1.54-1.42(m,2H).
Step C：1- (6- ((6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) amino) pyridin-3-yl) piperidines -4- Alcohol
By round-bottomed flask be filled with the bromo- 6- of 8- chloro- [1,2,4] triazole [1,5-a] pyridine (1.1g, 4.70mmol, example 1, Step A), 1- (6- aminopyridine -3- base) piperidines -4- alcohol (1.0g, 5.17mmol), cesium carbonate (3.1g, 9.41mmol) and Xantphos (0.16g, 0.282mmol, Strem) in Isosorbide-5-Nitrae-dioxane (50mL).Adding Pd (OAc)2(0.03g, Before 0.14mmol), this reactant mixture is carried out bubbling 15 minutes with nitrogen.This reaction is heated to about 80 DEG C and lasts about 16h. This reactant is cooled to ambient temperature and this solvent removed in a vacuum.By with 10-100%EtOAc/MeOH eluting Silica gel chromatography carries out purification to provide 1- (6- ((6- chloro- [1,2,4] triazole [1,5-a] pyridine -8- base) ammonia to this roughage Base) pyridin-3-yl) piperidines -4- alcohol 1.1g, 64% yield).LC/MS (table 1, method h) Rt=1.75min；MS m/z=345 (M+H)+.
Step D：1- (6- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) pyridin-3-yl) piperazine Pyridine -4- alcohol
Reaction bottle is filled with 1- (6- ((6- chloro- [1,2,4] triazole [1,5-a] in 1,4- dioxane (7.2mL) Pyridine -8- base) amino) pyridin-3-yl) piperidines -4- alcohol (0.25g, 0.73mmol).In THF (11.6mL, 5.80mmol) and Pd (dppf)Cl2Before cyclohexyl bromide solutions in (0.05g, 0.07mmol) add, by this bottle nitrogen bubbling.This is reacted It is heated to about 85 DEG C and last about 1h.This reactant is cooled to ambient temperature segmentation between EtOAc and water.By having of merging Machine part is washed with 1N aqueouss NaOH, through MgSO4It is dried, filter, and concentrate under reduced pressure.By this roughage through preparative (table 1, method y) purification is to provide 1- (6- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) pyrrole for HPLC Pyridine -3- base) piperidines -4- alcohol (0.01g, 11% yield).LC/MS (table 1, method h) Rt=2.21min；MSm/z=393 (M+H )+.CSF-1R enzyme IC50=A
Example #14：6- cyclohexyl-N- (1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1, 5-a] pyrazine -8- amine
Step A：6- cyclohexyl-N- (1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5- A] pyrazine -8- amine
Round-bottomed flask is filled with 6- cyclohexyl-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine, hydrochloric acid (0.40g, 0.99mmol, table D1.1), paraformaldehyde (0.06g, 1.98mmol), acetic acid (0.17mL, 2.98mmol) and the sodium triacetoxy borohydride (0.21g, 0.99mmol) in MeOH (9.93mL).Should Reaction is heated to about 50 DEG C and lasts about 18h.This reactant is cooled to ambient temperature and this solvent removed under vacuo.Should Residue is in aqueouss NaHCO of saturation3(20mL) segmentation and DCM (2x20mL) between.The organic moiety of merging is done through MgSO4 Dry, filter, and concentrate under reduced pressure.This roughage is passed through preparation HPLC (table 2, method 20) purification to provide 6- hexamethylene Base-N- (1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (0.032g, 9% yield).LC/MS (table 1, method h) Rt=1.65min；MS m/z=381 (M+H)+.CSF-1R enzyme IC50=A
Example #15：3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) propyl- 1- alcohol
Step A：The bromo- N- of 6- (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine
To 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine (0.989g, 3.56mmol, Noah's ark drugmaker) in DMF (18mL) DIEA (1.9ml, 10.6mmol) and 1H- pyrazoles -4- amine (0.44g, 5.34mmol, Kang Beibo are added in the solution in Ces Co., Ltd).This reaction is heated to about 95 DEG C and lasts about 3h.This reactant is cooled to ambient temperature and by this solvent true Aerial removal.Remaining residue is suspended in H2In O (20mL) and be stirred at room temperature overnight.The solid obtaining is filtered, It is suspended in again in EtOAc (20mL), and filter to provide the bromo- N- of the 6- of gray solid (1H- pyrazoles -4- base)-[1,2,4] Triazole [1,5-a] pyrazine -8- amine (0.9g, 90% yield).LC/MS (table 1, method h) Rt=1.52min；MS m/z=280 (M +H)+.
Step B：Tert-butyl 4- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- first Acid esters
To the bromo- N- of 6- (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (0.79g, 2.8mmol), N, N- lutidines -4- amine (0.03g, 0.28mmol) and TEA (0.59mL, 4.26mmol) is in the solution in DCM (19mL) Add Boc2O (0.62g, 2.84mmol).This mixture is stirred at room temperature about 4h.This solvent is removed in a vacuum.Logical Cross, with the silica gel chromatography of MeOH/DCM (0-3%) eluting, purification is carried out to provide white solid to remaining residue Tert-butyl 4- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- formic acid esters (0.72g, 66% Yield).LC/MS (table 1, method h) Rt=2.23min；MS m/z=378 (M-H)-.
Step C：6- cyclohexyl-N- (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine
By reaction bottle be filled with tert-butyl 4- in 1,4- dioxane (7.5mL) ((6- bromo- [1,2,4] triazole [1, 5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- formic acid esters (0.72g, 1.88mmol).In THF (22mL, 11.33mmol) and Pd(dppf)Cl2Before cyclohexyl bromide solutions in (0.14g, 0.19mmol) add, by this bottle nitrogen bubbling about 5min. This reaction is heated to about 75 DEG C and lasts about 30 minutes.This reactant is cooled to ambient temperature and in DCM (3x40mL) and satisfies Aqueouss NaHCO of sum3(40mL) segmentation between.The organic moiety MgSO that this is merged4It is dried, filter and dense under reduced pressure Contracting.Provide 6- cyclohexyl-N- by this roughage being carried out with purification with the silica gel chromatography of MeOH/DCM (0-10%) eluting (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (0.41g, 77% yield).LC/MS (table 1, method h) Rt =2.01min；MS m/z=284 (M+H)+.
Step D：3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) Propyl- 1- alcohol
Reaction bottle is filled with 6- cyclohexyl-N- (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine (0.12g, 0.43mmol), K2CO3(0.08g, 0.64mmol) and 3- iodine propyl- 1- alcohol in DMF (4.5mL) (1mL, 0.86mmol).This reaction is heated to 90 DEG C and lasts about 16h.Then by the 3- iodine propyl- 1- alcohol of 2 other equivalents (2mL, 0.86mmol) it is added in this reaction and continue stir about 4h at about 90 DEG C.This reactant is cooled to ambient temperature and leads to Cross preparation HPLC (table 1, method aa) purification to provide 3- (4- ((the 6- cyclohexyl-[1,2,4] triazole in pale solid [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) propyl- 1- alcohol (0.04g, 25% yield).LC/MS (table 1, method h) Rt=1.97min；MS m/z=342 (M+H)+.CSF-1R enzyme IC50=A
Example #16：Cis -4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrrole Azoles -1- base) cyclohexane-carboxylic acid
To cis-ethyl 4- (4- ((the 6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- in MeOH (0.6mL) Base) amino) -1H- pyrazol-1-yl) add 1N water in solution in naphthenic acid ester (0.05g, 0.12mmol, Table A .1.8) Property NaOH (0.25mL, 0.25mmol).This reaction is stirred at room temperature about 16h.This solvent is concentrated under reduced pressure, and will remain Remaining residue passes through preparation HPLC (table 1, method ab) purification to provide cis -4- (4- ((the 6- ring in pale solid Hexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) cyclohexane-carboxylic acid (0.018g, 35% product Rate).LC/MS (table 1, method h) Rt=2.27min；MS m/z=410 (M+H)+.CSF-1R enzyme IC50=A
Example #17：6- cyclohexyl-N- (1- ((2R, 4s, 6S)-lupetidine -4- base) -1H- pyrazoles -4- base) - [1,2,4] triazole [1,5-a] pyrazine -8- amine
Step A：Tert-butyl 4- (4- ((6- bromo- [1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base)-lupetidine -1- formic acid esters
To 6,8- bis- bromo- [1,2,4] triazole [1,5-a] pyrazine (1.54g, 5.54mmol, Noah's ark drugmaker) in DMF (20mL) tert-butyl 4- (4- amino -1H- pyrazol-1-yl)-lupetidine -1- formic acid esters are added in the solution in (1.79g, 6.10mmol prepare #10) and DIEA (1.16ml, 6.65mmol).This reactant mixture is heated to about 100 DEG C Last about 14h.This reaction is cooled to ambient temperature segmentation between water (40mL) and EtOAc (3x40mL).By merge Organic moiety is through Na2SO4It is dried, filter, and concentrate under reduced pressure.This residue is passed through with EtOAc/ petroleum ether (0-10%) The Silica gel chromatography of eluting is to provide tert-butyl 4- (4- ((6- bromo- [1,2,4] triazole [1,5-a] pyrrole in yellow solid Piperazine -8- base) amino) -1H- pyrazol-1-yl) -2,6- lupetidine -1- formic acid esters (2.5g, 92% yield).LC/MS (table 1, Method w) Rt=1.50min；MS m/z=492 (M+H)+.
Step B：(2R, 4s, 6S)-tert-butyl 4- (4- ((6- (hexamethylene -1- alkene -1- base)-[1,2,4] triazole [1,5-a] Pyrazine -8- base) amino) -1H- pyrazol-1-yl)-lupetidine -1- formic acid esters
Round-bottomed flask is filled with tert-butyl 4- (the 4- ((6- bromo- [1,2,4] three in DMF (12mL) and water (9mL) Azoles [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2,6- lupetidine -1- formic acid esters (2.4g, 4.88mmol), 2- (hexamethylene -1- alkene -1- base) -4,4,5,5- tetramethyl -1,3,2- dioxaborolanes (1.220g, 5.86mmol, Noah's ark drugmaker), Na2CO3(1.5g, 14.6mmol) and Pd (Ph3P)4(0.56g, 0.488mmol).Should Reaction is heated to about 80 DEG C and lasts about 14h.By this reaction be cooled to ambient temperature and water (40mL) and EtOAc (3x50mL) it Between segmentation.By the organic moiety merging through Na2SO4It is dried, filter, and concentrate under reduced pressure.By this residue by using EtOAc/ The silica gel chromatography of petroleum ether (0-10%) eluting carries out purification to provide racemic product.This racemate is stood preparative Chiral SFC (table 2, method 19) is to provide (2R, 4s, 6S)-tert-butyl 4- (4- ((6- (hexamethylene -1- alkene -1- of white solid Base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl)-lupetidine -1- formic acid esters (0.71g, 29% yield).LC/MS (table 2, method 19) Rt=3.12min；MS m/z=493 (M+H)+.
Step C：(2R, 4r, 6S)-tert-butyl 4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) Amino) -1H- pyrazol-1-yl)-lupetidine -1- formic acid esters
To (2R, 6S)-tert-butyl 4- (4- ((6- (hexamethylene -1- alkene -1- base)-[1,2,4] triazole [1,5-a] pyrazine -8- Base) amino) -1H- pyrazol-1-yl) -2,6- lupetidine -1- formic acid esters (200mg, 0.41mmol) is in MeOH (5mL), THF (5mL) add 10%Pd/C (216mg, 2.03mmol) in the solution and in the mixture of AcOH (0.25mL).At room temperature, In a hydrogen atmosphere, by this reaction stir about 16hr.This reactant mixture is passed through kieselguhrPad is filtered, And under reduced pressure concentrate with white solid is provided (2R, 6S)-tert-butyl 4- (4- ((6- cyclohexyl-[1,2,4] triazole [1, 5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2,6- lupetidine -1- formic acid esters (170mg, 85% yield).
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.25(s,1H),8.13(s,1H),7.93(s,1H),7.77 (s,1H),4.77-4.72(m,1H),4.61-4.56(m,2H),2.67-2.61(m,1H),2.17-2.04(m,8H),1.91- 1.95(m,4H),1.51(s,9H),1.47(s,3H),1.44(s,3H),1.37-1.29(m,2H).
Step D：6- cyclohexyl-N- (1- ((2R, 4s, 6S)-lupetidine -4- base) -1H- pyrazoles -4- base) - [1,2,4] triazole [1,5-a] pyrazine -8- amine
To (2R, 4s, 6S)-tert-butyl 4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) ammonia Base) -1H- pyrazol-1-yl)-solution in DCM (15mL) for 2,6- lupetidine -1- formic acid esters (170mg, 0.344mmol) Middle interpolation TFA (5mL, 64.9mmol).This reactant mixture is stirred at room temperature about 2h.This reaction is stirred at room temperature about 16h.This solvent is concentrated under reduced pressure and by remaining residue DCM and saturation aqueouss NaHCO3Between segmentation.Should Organic moiety is dried through anhydrous Na 2SO4, filters, and concentrates under reduced pressure.By the solid obtaining from EtOAc (2mL) recrystallize with There is provided the 6- cyclohexyl-N- (1- ((2R, 4s, 6S)-lupetidine -4- base) -1H- pyrazoles -4- base) of white solid - [1,2,4] triazole [1,5-a] pyrazine -8- amine (52mg, 39% yield).LC/MS (table 1, method w) Rt=2.69min；MS m/z =395 (M+H)+.CSF-1R enzyme IC50=A.

Claims (20)

1. a kind of compound with chemical formula (I)
Wherein
U is CR1Or N；
X is CR2Or N；
Y is CR3Or N；
Z is CR4Or N；
R1It is independently H or deuterium；
R2It is H, deuterium, optionally substituted (C1-C3) alkyl or CF3；
R3It is H, deuterium or optionally substituted (C1-C3) alkyl；
R4It is H or deuterium；
R5It is-R501-L-R502Wherein
R501It is key ,-O- ,-OCH2- or optionally substituted (C1-C3) alkylidene,
L be-C (=O)-,-CH2N (H) C (=O)-,-N (H) C (=O)-or-N (H) S (O)2；Or
L is key and R502It is-CN；Or
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is optionally substituted phenyl, the heterocycle of optionally substituted heteroaryl, optionally substituted saturation or fractional saturation Base or optionally substituted saturation or fractional saturation (C3-C7) cycloalkyl and L2It is key ,-CH2N(Ra)-、-CH2N(Ra) C(O)-、-N(Ra)C(O)-、-N(Ra)S(O)2- or-N (Ra)-；Or
L1It is the heterocyclic radical of saturation or fractional saturation, this heterocyclic radical comprises one or more hetero atoms, and wherein at least one is miscellaneous former Son is nitrogen and L2It is key, C (O) or-S (O)2-；
R502It is H, CF3, OH, optionally substituted (C1-C6) alkyl, optionally substituted thiazolinyl, optionally substituted alkynyl, CN or optionally substituted (C3-C6) cycloalkenyl group；
R6It is optionally substituted (C1-C6) alkyl, optionally substituted (C3-C12) cycloalkyl, optionally substituted phenyl, appoint Heteroaryl or optionally substituted heterocyclic radical that selection of land replaces；Or
R6It is-R601-R602, wherein R601Be attached to-N (H)-and
R601It is optionally substituted heteroaryl；
R602It is N (Ra)2, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl or optionally replace Heterocyclic radical；And
RaIt is independently H or optionally substituted (C1-C6) alkyl；
Its condition is this compound is not 2- (3- { 8- [5- (morpholine -4- carbonyl)-pyridine -2- base amino]-imidazoles [1,2-a] pyrrole Pyridine -6- base }-phenyl)-N- (the fluoro- 4- hydroxy-4-methyl of 5,5,5- tri--amyl- 2- alkynyl)-acetamide.
2. compound according to claim 1, wherein
U is CR1Or N；
X is CR2Or N；
Y is CR3Or N；
Z is CR4Or N；
R1It is independently H or deuterium；
R2It is H, deuterium, optionally substituted (C1-C3) alkyl or CF3；
R3It is H, deuterium or optionally substituted (C1-C3) alkyl；
R4It is H or deuterium；
R5It is-R501-L-R502, wherein
R501It is key ,-O- ,-OCH2- or optionally substituted (C1-C3) alkylidene,
L be-C (=O)-,-CH2N (H) C (=O)-,-N (H) C (=O)-or-N (H) S (O)2；Or
L is key and R502It is-CN；Or
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is optionally substituted phenyl, the heterocycle of optionally substituted heteroaryl, optionally substituted saturation or fractional saturation Base or optionally substituted saturation or fractional saturation (C3-C6) cycloalkyl and L2It is key ,-CH2N(Ra)-、-CH2N(Ra) C(O)-、-N(Ra)C(O)-、-N(Ra)S(O)2- or-N (Ra)-；Or
L1It is the heterocyclic radical of saturation or fractional saturation, this heterocyclic radical comprises one or more hetero atoms, and wherein at least one is miscellaneous former Son is nitrogen and L2It is key, C (O) or-S (O)2-；
R502It is H, optionally substituted thiazolinyl, optionally substituted alkynyl, CN or optionally substituted (C3-C6) cycloalkenyl group；
R6It is optionally substituted (C1-C6) alkyl, optionally substituted (C3-C12) cycloalkyl, optionally substituted phenyl, appoint Heteroaryl or optionally substituted heterocyclic radical that selection of land replaces；And
RaIt is independently H or optionally substituted (C1-C6) alkyl.
3. compound as claimed in claim 1, wherein
L be-C (=O)-,-CH2N (H) C (=O)-,-N (H) C (=O)-or-S (O)2；And R502It is H ,-CH=CH2Or-C ≡CH；Or
L is key and R502It is-CN；Or
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is optionally substituted phenyl, optionally substituted heteroaryl or optionally substituted saturation or fractional saturation (C3-C6) cycloalkyl and L2It is-CH2N(Ra)-、-CH2N(Ra)C(O)-、-N(Ra)C(O)-、-N(Ra)S(O)2- or-N (Ra)-； Or
L1Be optionally substituted heteroaryl, optionally substituted nitrogen heterocyclic heptyl, optionally substituted azetidinyl, Optionally substituted morpholinyl, optionally substituted oxazepine cycloheptyl alkyl, optionally substituted piperidyl, optionally replace Pyrrolidinyl, optionally substituted tetrahydrofuran base or optionally substituted THP trtrahydropyranyl, and L2Be key, C (O) or- S(O)2-.
4. compound as claimed in claim 2, wherein R6It is optionally substituted (C1-C6) alkyl, optionally substituted benzene Base, optionally substituted bicyclo- [1.1.1] pentynyl, optionally substituted 1,2,4 di azolies, optionally substituted pyrazoles Base, optionally substituted pyridazinyl, optionally substituted pyridine radicals, 4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one, 3,4- dihydroquinoline -2 (1H) -one, 2H- benzo [b] [1,4] piperazine -3 (4H) -one or 6,7- dihydro -4H- pyrazolo [5,1- C] [1,4] piperazine base.
5. compound as claimed in claim 3, wherein R6Optionally be substituted by one or more substituents, this or these take Dai Ji is independently selected from (C1-C3) alkyl, (C1-C3) alkoxyl, optionally substituted imidazolone or morpholinyl.
6. compound as claimed in claim 4, wherein-L-R502Form-CN ,-CH2N (H) C (=O) CH=CH2,-C (=O) CH=CH2,-N (H) C (=O) CH=CH2,-N (H) CN or-S (O)2CH=CH2.
7. compound as claimed in claim 1, wherein this compound are
N- (3- (8- ((4- morphlinophenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) benzyl) Acrylamide；
N- (3- (8- (bicyclo- [1.1.1] amyl- 1- base amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) benzyl Base) acrylamide；
N- (3- (8- (bicyclo- [1.1.1] amyl- 1- base amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) benzene Base) acrylamide；
1- (3- (8- ((3,4- Dimethoxyphenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) pyrrole Cough up alkane -1- base) propyl- 2- alkene -1- ketone；
8- ((5- (1- acryloyl pyrrolidin-3-yl) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) - 4,5- dihydro -1H- benzo [b] azatropylidene -2 (3H) -one；
1- (3- (8- ((4- morpholino pyridine -2- base) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) pyrrole Cough up alkane -1- base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((5- methoxyl group pyridazine -3- base) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyridine -5- base) Pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
N- (2- (8- (bicyclo- [1.1.1] amyl- 1- base amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -5- base) benzene Base) acrylamide；
1- ((3R) -3- (8- ((3,4- Dimethoxyphenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -6- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- ((3S) -3- (8- ((3,4- Dimethoxyphenyl) amino) -1,8a- dihydro-[1,2,4] triazole [1,5-a] pyrazine -6- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
8- ((6- (1- Antiepilepsirin -3- base)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -4,5- dihydro -1H- Benzo [b] azatropylidene -2 (3H) -one；
N- (3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] triazole [1, 5-a] pyrazine -6- base) phenyl) acrylamide；
N- (3- (8- ((2- oxo -2,3,4,5- tetrahydrochysene -1H- benzo [b] azatropylidene -8- base) amino)-[1,2,4] triazole [1, 5-a] pyrazine -6- base) benzyl) acrylamide；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine -1- Base) propyl- 2- alkene -1- ketone；
7- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -3,4- dihydro quinoline Quinoline -2 (1H) -one；
6- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -2H- benzo [b] [1,4] piperazine -3 (4H) -one；
8- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) -4,5- dihydro - 1H- benzo [b] azatropylidene -2 (3H) -one；
(S) -8- ((6- (1- acryloyl pyrrolidin-3-yl) imidazo [1,2-a] pyrazine -8- base) amino) -4,5- dihydro -1H- Benzo [b] azatropylidene -2 (3H) -one；
(R) -8- ((6- (1- acryloyl pyrrolidin-3-yl) imidazo [1,2-a] pyrazine -8- base) amino) -4,5- dihydro -1H- Benzo [b] azatropylidene -2 (3H) -one；
(S)-N- (3,4- Dimethoxyphenyl) -6- (1- (vinylsulfonyl) pyrrolidin-3-yl)-[1,2,4] triazole [1,5- A] pyrazine -8- amine；
1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] Pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridazine -3- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) Propyl- 2- alkene -1- ketone；
1- (3- (8- (methylamino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((2- methoxy ethyl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((5- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) Propyl- 2- alkene -1- ketone；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) Propyl- 2- alkene -1- ketone；
1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] Pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone；
(S) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
(R) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridin-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) piperidin-1-yl) Propyl- 2- alkene -1- ketone；
1- (3- (8- ((6- morpholino pyridin-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- Base) propyl- 2- alkene -1- ketone；
1- (3- (8- ((3- isopropyl -1,2,4- diazole -5- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperazine Pyridine -1- base) propyl- 2- alkene -1- ketone；
N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Cyclohexyl) acrylamide；
N- ((1S, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) methyl)-[1,2,4] triazole [1,5-a] pyridine -6- base) Cyclohexyl) acrylamide；
1- (3- (8- ((3- methyl isophthalic acid, 2,4- diazole -5- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperazine Pyridine -1- base) propyl- 2- alkene -1- ketone；
N- ((1S, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Cyclohexyl) cyanamide；
3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidines -1- formonitrile HCN；
3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) pyrrolidine -1- first Nitrile；
1- (4- ((6- (1- acryloyl pyrrolidin-3-yl)-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) phenyl) -3- Methylimidazole. quinoline -2- ketone；
3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- first Nitrile；
N- ((1R, 3S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) Cyclopenta) acrylamide；
N- ((1S) -3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) ring penta Base) acrylamide；
3- (8- ((6,7- dihydro -4H- pyrazolo [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyrrole Pyridine -6- base) piperidines -1- formonitrile HCN；
(S) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
(R) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((1- methyl isophthalic acid H- pyrazole-3-yl) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrrolidine -1- Base) propyl- 2- alkene -1- ketone；
(S) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
(R) -1- (3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) pyrroles Alkane -1- base) propyl- 2- alkene -1- ketone；
(S) -1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1, 5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone；
1- (3- (8- ((6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine -2- base) amino) imidazo [1,2-b] pyridazine -6- Base) pyrrolidin-1-yl) propyl- 2- alkene -1- ketone；Or
(R) -1- (3- (8- ((6,7- dihydro -4H- pyrazolo [5,1-c] [1,4] piperazine -2- base) amino)-[1,2,4] triazole [1,5-a] pyridine -6- base) piperidin-1-yl) propyl- 2- alkene -1- ketone.
8. compound according to claim 1, wherein
R5It is-R501-L-R502, wherein
R501It is key；
L is-L1-L2, wherein L1It is attached to R501, wherein
L1It is (the C of optionally substituted saturation or fractional saturation3-C7) cycloalkyl and L2It is key-CH2N(Ra) C (O)-or- N(Ra)C(O)-；And
R502It is H, CF3, OH, optionally substituted (C1-C6) alkyl, optionally substituted thiazolinyl, optionally substituted alkynyl, CN or optionally substituted (C3-C6) cycloalkenyl group.
9. compound according to claim 8, wherein
R6It is optionally substituted (C1-C6) alkyl, optionally substituted (C3-C12) cycloalkyl, optionally substituted phenyl, appoint Pyrazolyl that selection of land replaces, optionally substituted 6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] piperazine base, optionally substituted 4,5,6,7- tetrahydro-pyrazole [1,5-a] pyrazinyl；Or
R6It is-R601-R602, wherein R601Be attached to-N (H)-and
R601It is optionally substituted pyrazolyl or optionally substituted pyridine radicals；
R602It is N (Ra)2, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) cycloalkyl, optionally substituted Azetidinyl, optionally substituted morpholinyl, optionally substituted piperidyl or optionally substituted THP trtrahydropyranyl.
10. compound according to claim 9, wherein R1It is H.
11. compounds according to claim 10, wherein X is N or CR2, wherein R2It is H, optionally substituted (C1-C3) alkane Base or CF3.
12. compounds according to claim 11, wherein R3It is H, deuterium or optionally substituted (C1-C3) alkyl.
13. compounds according to claim 12, wherein U is CH.
14. compounds according to claim 13, wherein X is N.
15. compounds as claimed in claim 1, wherein this compound are
4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2- methyl butyl- 2- alcohol；
6- cyclohexyl-N- (1- (tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- Amine；
6- cyclohexyl-N- (1- (2,2,6,6- tetramethyl tetrahydrochysene -2H- pyrans -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclohexyl-N- (1- (oxetanes -3- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- Amine；
(1R, 4R) -4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) ring Hexanol；
(1S, 4S) -4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) ring Hexanol；
6- cyclohexyl-N- (1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
(6- cyclohexyl-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclopenta-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclohexyl-N- (1- isopropyl -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- (4,4- Dimethylcyclohexyl)-N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- ((1R, 4R) -4- methylcyclohexyl)-[1,2,4] triazole [1,5-a] pyrazine - 8- amine；
N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- ((1S, 4S) -4- methylcyclohexyl)-[1,2,4] triazole [1,5-a] pyrazine - 8- amine；
N- (1- methyl isophthalic acid H- pyrazoles -4- base) -6- ((1r, 4r) -4- (trifluoromethyl) cyclohexyl)-[1,2,4] triazole [1,5-a] Pyrazine -8- amine；
N- (6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine；
6- cyclohexyl-N- (5- methyl -4,5,6,7- tetrahydro-pyrazole simultaneously [1,5-a] pyrazine -2- base)-[1,2,4] triazole [1,5-a] Pyridine -8- amine；
6- cyclopenta-N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclopenta-N- (5- methyl -4,5,6,7- tetrahydro-pyrazole simultaneously [1,5-a] pyrazine -2- base)-[1,2,4] triazole [1,5-a] Pyridine -8- amine；
1- (4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) piperidines -1- Base) ethyl ketone；
4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl)-N- methyl piperazine Pyridine -1- Methanamide；
(1S, 3S) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) ring Hexanol；
(1R, 3R) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) ring Hexanol；
(1R, 3S) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) ring Hexanol；
(1S, 3R) -3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) ring Hexanol；
(1R, 3R) -3- (8- ((1- methyl isophthalic acid H- pyrazoles -4- base) amino)-[1,2,4] triazole [1,5-a] pyrazine -6- base) hexamethylene Alcohol；
1- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) -2- methyl-prop Alkane -2- alcohol；
N- (6- cyclopenta-[1,2,4] triazole [1,5-a] pyridine -8- base) -6,7- dihydro -4H- pyrazoles [5,1-c] [1,4] Piperazine -2- amine；
1- (6- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyridine -8- base) amino) pyridin-3-yl) piperidines -4- alcohol；
6- cyclohexyl-N- (1- (1- methyl piperidine -4- base) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- Amine；
(1S, 4S)-ethyl 4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazoles -1- Base) naphthenic acid ester；
6- cyclopenta-N- (1- (piperidin-4-yl) -1H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
6- cyclohexyl-N- (1- methyl isophthalic acid H- pyrazoles -4- base)-[1,2,4] triazole [1,5-a] pyrazine -8- amine；
Cis -4- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) hexamethylene Alkane carboxylic acid；Or
3- (4- ((6- cyclohexyl-[1,2,4] triazole [1,5-a] pyrazine -8- base) amino) -1H- pyrazol-1-yl) propyl- 1- alcohol.
A kind of 16. methods treating disease, the method include to its patient in need is given therapeutically effective amount as right Require the compound described in 1.
17. methods according to claim 16, wherein this disease are rheumatoid arthritiss, juvenile rheumatoid joint Inflammation, osteoarthritis, Crohn disease, inflammatory bowel, irritable bowel syndrome, ulcerative enteritis, psoriasis arthropathica, psoriasises, Ankylosing spondylitises, interstitial cystitiss, asthma, systemic lupus erythematosus (sle), lupus nephritis, B cell chronic lymphocytic Lymphoma, multiple sclerosis, chronic lymphocytic leukemia, small lymphocytic lymphoma, lymphoma mantle cell, B are thin Born of the same parents' non-Hodgkin lymphoma, the B cell sample diffusivity large B cell lymphoid tumor of activation, multiple myeloma, diffusivity large B cell Lymphoma, follicular lymphoma, hairy cell leukemia or LBL.
A kind of 18. test kits of the product comprising to pack, the product of this packaging comprises various ingredients, by these components with as right The compound described in 1 is required to give together, disorderly for treating autoimmune.
19. test kits according to claim 18, the product of wherein this packaging comprises compound as claimed in claim 1 And operation instructions.
A kind of 20. pharmaceutical compositions, pharmaceutically acceptable including compound according to claim 1 and one or more Excipient.
CN201580031633.1A 2014-04-17 2015-04-16 Heterocyclic kinase inhibitors Pending CN106459045A (en)

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CNPCT/CN2014/075560 2014-04-17
PCT/CN2014/075560 WO2015157955A1 (en) 2014-04-17 2014-04-17 Heterocyclic btk inhibit ors
PCT/CN2015/076766 WO2015158283A1 (en) 2014-04-17 2015-04-16 Heterocyclic kinase inhibitors

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